Methylation of DNA is the best-known mode of epigenetic regulation (turning genes on and off). Methylation patterns are stable unless they are actively changed, and can persist over decades, even across generations.
Four years ago, biostatistician Steve Horvath of UCLA identified a set of 353 methylation sites that are best-correlated with human (chronological) age. These are sites where genes are turned on and off at particular stages of life. A computer analysis of a gene sample (from blood or skin or even urine) can determine a person’s age within about two years.
Two reasons the Horvath Clock is important. First, it is the best measure we have of a person’s biological age, so it provides an objective measure of whether our anti-aging interventions are working. Say you’re excited about a new drug and you want to know whether it really makes people younger. Before the Horvath clock, you had to give it to thousands of people and wait a long time to see if fewer of them were dying, compared to people who did not get the drug. The Horvath clock is a huge shortcut. You can give the drug to just a few people and measure their Horvath (methylation) age before and after. With just a few dozen people over a two-year period, you can get a very good idea whether your drug is working.
Second, there is evidence and theory to support the idea that the methylation sites that Horvath identified are not just markers of aging but causes of aging. That means that if we can figure out how to get inside the cell nucleus and re-configure the methylation patterns on the chromosomes, we should be able to address a root cause of aging. (Before we get too excited: “Gene therapy” has been around 20 years but is still in a developmental stage; “epigenetic therapy” is what we need, and it does not yet exist, but is technically feasible using genetically engineered viruses and CRISPR.)
In 2012-2013, three papers appeared proposing the idea that the deep cause of aging (in humans and many other higher animals) is an epigenetic program [Johnson, Mitteldorf, Rando]. Genes are turned on and off at various stages of life, producing growth, development and aging in seamless sequence. (A fourth paper by Blagosklonny proposed a similar idea, but focused on the role of a single transcription factor controlling gene expression (mTOR) and shied away from the conclusion that natural selection might have preferred aging affirmatively. Here’s an earlier presentiment by Blagosklonny.)
It’s a powerful hypothesis that proposes to resolve evolutionary and metabolic questions alike. It contains a seed of a prescription for anti-aging research—although epigenetics has proved to be so complicated that practical modification of the body’s gene expression schedule may require a lot more groundwork.
Unbeknownst to any of us working on these theoretical papers, Steve Horvath was already working on calibration and measurement of the epigenetic aging clock, and he published his basic result by the end of 2013.
One remarkable property of the Horvath clock is that it is more accurate than chronological age for predicting who will contract aging diseases and who will die. Even though the clock was derived with an algorithm that matched the output clock age as closely as possible to chronological age, the result proved to contain more information than chronological age. “In deriving the clock, chronological age was used as a proxy for biological age.” People whose “methylation age” is greater than their chronological age are likely to suffer health deterioration and to die sooner than people whose methylation age is less than their chronological age.
Horvath has openly shared his methodology and his computer program. Based on the Horvath clock, a California company began last year to offer a commercial test for methylation age. You can send a blood or urine sample to Zymo Research.
Candidate aging clocks
Horvath describes how he came up with the idea of a methylation clock by a process of elimination, beginning with four candidate clocks:
Gene expression profile
Telomere length – This had been measured easily and cheaply for more than a decade, but its correlation with chronological age (and with mortality) is not strong enough to be useful as a biological clock.
Gene expression profile: Which genes are being transcribed into RNA at a given time? This can be measured by extracting RNA, and turns out to be highly tissue-specific. In other words, it varies according to which part of the body you’re looking at.
Proteomic data: Genes, once transcribed, are translated into proteins. Some of these proteins stay in the cell while others circulate through the body. Gene CHIP technology measures levels of different proteins reliably and inexpensively.
DNA Methylation: Easier to measure than (2) or (3). Methylation is only one of many mechanisms controlling gene expression, but it is one of the most persistent. Horvath found that a subset of DNA methylation sites seems to be characteristic of age no matter where in the body they are measured.
What is DNA methylation?
Adjacent to many genes is a promoter site, a location on the same chromosome which stores temporary information about whether the gene is turned on or off. Promoter sites contain the base sequence C-G-C-G-C-G-C repeated. This is called a CpG island (where the “p” just tells you that the C is linked to G on the same strand, rather than being linked across strands, in which C is paired with G.)
C stands for “Cytosine”, and the Cytosine molecule can be modified by adding an extra methyl group (CH3) to form 5-methyl Cytosine.
The cell has molecular workers that are deployed to go around specifically adding methyl groups in some parts of the DNA or removing them in others. The bottom line is that methylated Cytosine is a sign that says “don’t transcribe the adjacent gene.” When the methyl groups are removed, it is a signal that the gene are to be transcribed once more.
Enzymes called methyl transferases are deployed to precise regions of the genome to turn genes on and off. Methylation can be transient. There is evidence for circadian cycles of methylation. Or it can be quite long-lasting. Methylation patterns can persist for decades, and are copied when cells replicate, so that methylation patterns can be passed to offspring as part of one’s epigenetic legacy. Inherited methylation sites are the exception however; most of the genome is programmed fresh with age-zero, pluripotent methylation patterns when egg and sperm cells are generated.
How the methylation clock works
Using a standard statistical algorithm, Horvath identified 353 CpG sites that were most strongly correlated with chronological age, no matter where in the body he looked. The same algorithm provided 353 numbers to be multiplied by methylation levels at each site, then added up to produce a number. The number is not directly a measure of age, but in the last step a table is used (an empirically-derived curve) to associate the number with an age.
This is the raw output of the function before it is transformed into an age. Notice that methylation changes very rapidly during the first 5 years of life, gradually slowing during the growth phase and straightening out to constant slope after about age 18.
Even though the Horvath clock was designed to be independent of what part of the body DNA was drawn from, some variations appear. Most noticeable is female breast tissue, which ages faster than the rest of the body, and brain tissue, which ages more slowly. Blood and bone tissue tend to age a little faster. (Sperm and egg cells are “age zero” no matter the age of the person from whom the germ cells were drawn. Placentas from women of all ages are age zero.) Similarly, induced stem cells (using the 4 Yamanaka factors) have zero age. In contrast, a similar treatment can change one differentiated cell type into another, for example, turning a skin cell into a neuron. This does not affect epigentic age.
Liver cells tend to be older than the rest of the body in people who are overweight, and younger than the rest of the body in people who are underweight. Other tissues don’t seem to show this relationship. For example, fat cells do not have older methylation ages in people who are obese. And, perhaps surprisingly, weight loss does not reverse the accelerated methylation age of the liver (at least, not within the 9-month time frame of the one study looking at this).
Studies have been done correlating methylation age with various diseases and, of course, mortality. Corrections are made for every kind of environmental factor, including smoking, obesity, exercise, workplace hazards, etc, called collectively the “extrinsic factors”. The result is that methylation age rises with extrinsic factors, and independently methylation age is also correlated with intrinsic (genetic) factors that affect lifespan. Horvath estimates that genetics controls 40% of the variation in methylation age (as it differs from chronological age).
Men are slightly older than women in methylation age. This is already evident by age 2. Delayed menopause is associated with lower epigenetic age. Cognitive function correlates inversely with methylation age of the brain.
Speaking before Horvath at the same conference, Jim Watson claims there are many supplements and medications that can slow the Horvath clock. The one he focuses on is metformin, which, he says, has epigenetic effects via an entirely different pathway from lowering blood sugar (the purpose for which it has been prescribed to tens of millions of diabetics).
Here’s a curious clue: There is a tiny number of children who never develop or grow, and continue to look like babies through age 20 and perhaps beyond. These children have normal methylation age. Whatever it is that blocks their growth, it is not the methylation changes in their DNA. Does this mean that there are other epigenetic controls, more powerful than methylation, that control growth and development? Or does it mean that children with this syndrome have normal epigenetic development, but something downstream from gene expression is blocking their growth? Conversely, Hutchinson-Gilford progeria is caused by a defect in the LMNA gene which causes children to age and die before they even grow up. Hutchinson-Gilford children have normal methylation ages by the Horvath clock.
Radiation, like smoking and exposure to environmental oxidation, tends to age the body faster. This is independent of methylation age—which is unaffected by radiation. Neither smoking nor radiation exposure affect epigenetic age. HIV also accelerates aging, and HIV does affect methylation age.
Methylation age and telomere age are both correlated with chronological age, and they both predict mortality and morbidity independent of chronological age. But the two measures are not correlated with each other. In other words, the information contained in the methylation clock and in measures of telomere length complement one another to offer a better predictor of future aging decline than either of them separately.
Diet has a weak effect on methylation age. Very high carbohydrate, very low protein diets are noticeably terrible. Beyond this, there seem to be two sweet spots: one for the Ornish-style protein-restricted diet and one for the Zone/Atkins style diet. Weak evidence to be sure, but suggestive that they both work.
“The epigenetic clock is broken in cancer tissue.” [ref]
Building on the original clock
The original clock was optimized to track chronological age, and yet it fortuitously provided more information than chronological age. In a second iteration, Horvath set out explicitly to track biological age. He used historic blood samples from the 1990s, and paired them with hospital records and death certificates to search for methylation sites that correlate best with aging-related health outcomes. The result was the phenotypic clock, DNAm phenoAge. This uses 513 methylation sites to predict
(loss of) physical strength
(loss of) cognitive ability
On the drawing board: An epigenetic clock specialized to work well with skin and blood cells, (which are the most accessible). (Enough skin cells can be scraped painlessly from the inside of your mouth (buccal epithelial cells) to do a DNAm test.)
Connection to Parabiosis and Plasma Transfusions
Several groups have begun to experiment with transfusions of blood plasma from a young donor as a possible path to rejuvenation. Horvath reports an encouraging finding: Sometimes older people contract a form of leukemia that requires a blood and marrow transfusion (including the stem cells that give rise to new blood) from a donor. The finding is that after this treatment, the blood of the patient continues to show the methylation age of the donor, not the patient.
Epigenetic Aging and Telomere Aging Bound to a See-Saw Relationship
(This was the most exciting new result for me personally, because it relates to an idea I have held dear for more than a decade.)
Methylation age is older or younger than chronological age in different people, generally by about +2 years. 40% of the variation is due to genetics. Some common genetic variants can make the clock run faster or slower. The most prominent genetic variants link telomere aging to methylation aging. The faster your epigenetic clock runs, the longer your telomeres. The slower your epigenetic clock runs, the shorter your telomeres. [preprint]
There’s a word for this in the genetic theory of aging. It’s called Antagonistic Pleiotropy. Back in 1957, George Williams theorized that the genes causing aging ought to have simultaneous beneficial and detrimental effects. That would explain why natural selection has permitted aging to occur, despite the fact that it cuts off fitness. Williams said: Nature had no choice but to accept the genes that cause aging because there was no other way to get the benefits of these same genes (which he surmised ought to enhance fertility).
My theory of Antagonistic Pleiotropy is that it is not a situation of “forced choice”; rather, aging is important for the health of the community, and mother nature has been faced with the dilemma: how to keep aging in place despite efficient natural selection against it on the individual level. Aging is so important to the community that evolution has been motivated to find ways to keep it in place, despite the short-term temptation for natural selection to favor those with longer lives (thus greater opportunities to leave offspring). In my hypothesis, evolution invented pleiotropy to address this problem. The telomerase-epigenetic clock connection is an example. There is no physically necessary connection between telomerase and epigenetic aging, but the two have evolved a see-saw link so that it is more difficult to mutate aging away.
This also relates to my coverage last fall of the telomerase-cancer connection. At the time, I was scratching my head, why should genetic variants that lengthen telomeres be associated with higher rates of some cancers? Here is a clue: The same genetic variants that lengthen telomeres also accelerate the epigenetic aging program. The specific example of a cancer that is most closely tied to higher telomerase levels is melanoma, which is a cancer that is less sensitive to age than other cancers. People tend to get melanoma earlier in life than other skin cancers. Therefore, I predict that other pleiotropic links will be found between these genetic variants that promote longer telomeres and other mechanisms linked specifically to melanoma.
The Bottom Line
All these data in a field so new is a tribute to Horvath’s industriousness and to the promise and fruitfulness of a new methodology.
The data so far suggest that methylation programming is a big part of the driver of aging, but not the whole story. Smoking affects life expectancy, but it doesn’t affect methylation age. Weight loss benefits life expectancy, but it is invisible to methylation age. Most curious are those children who fail to develop, or age prematurely, even though their methylation age is progressing on schedule.
What does it mean that radiation ages the body without advancing the methylation clock? Perhaps that accumulation of damage is part of the phenotype of aging, though I remain hopeful that the body remains capable of undoing that damage even late in life, if it is re-programmed to want to do so. What does it mean that AIDS advances the aging clock? Perhaps that the immune system is a central signaling mechanism in the aging process.
So, it’s “methylation plus”. Plus what? Not just methylation plus damage”; though we can certainly shorten our lifespan with radiation or smoking, we can’t increase our lifespan by avoiding toxins. “Methylation plus other epigenetic programs”—this would be my first guess. “Methylation plus mitochondrial state” would be a close second. Methylation is all in the nucleus, and the cytoplasm of the cell seems to store independent information, and can even re-program the state of the nucleus, as suggested by parabiosis experiments. There is also evidence for“Methylation plus telomere shortening”.
The Most Promising Way Forward for Anti-Aging Science Today
We now have many effective interventions (mostly of small effect) for longevity and preventive care. Most readers of this blog take more than one supplement each day; some of us (I confess) take very many. We make an unthinking assumption that “more is better”, or rather that if A is beneficial and B is beneficial then if we take A and B we can get the benefits of both. We don’t think to question or deconstruct this reasoning. It is rooted in a reductionism that works pretty well in the physical sciences, much less well in biology.
We know that the benefits of all these interventions don’t just add up like numbers in a spreadsheet, but we continue to act as though this were our reality.
The truth is that we know almost nothing about the cross-talk among different health interventions. The reasons so few experiments have been done are plain enough, but the situation has become untenable. There is an urgent need to understand the interactions among treatments. We might begin with those that are individually most promising, but expect surprises. The combinations that offer the greatest longevity benefits may turn out to be pieced together from components that individually have little or no effect.
I might have said ‘the most promising way forward for medical research today, because I believe that anti-aging science is the most productive area of medical research. If you are reading this page, you probably know this already, but we all take comfort in confirmation of what we already know. So:
Prevention is more cost-effective than treatment. The root cause of most disease in the developed world is aging. This point has been made decisively [for example], most eloquently by Aubrey de Grey. (The root cause of most disease in the third world is poverty, and ending poverty is also an essential imperative, but it is not a subject for medical research.)
The problem of interactions has been neglected for a number of reasons:
Unconscious linear thinking
The dizzying number of combinations that need to be studied
The want of a guiding paradigm that would provide context for individual studies
Scientific inertia: researchers are more likely to study (and funders are more likely to support) research programs that are established and proven
But the problem is potentially of great import. We expect a great deal of redundancy among the mechanisms of action of various interventions we know about. Taking two or three or four drugs that address the same biological pathway is likely to be a costly waste. More rarely, longevity drugs may interact in ways that actually interfere and reduce overall effectiveness.
But we have good reason to hope that in rare cases there are combinations that are more than the sum of their parts. These fortuitous combinations synergize to offer greater benefits than they provide separately. Finding a few such combinations would be a jackpot that justifies many, many expected null results.
The huge number of possibilities to be covered
If we begin with 30 individual interventions, there are 435 pairs of interactions and 4060 combinations of three and 27,405 combinations of four. If we think traditionally, each one of these combinations is a research program in itself, requiring at least several person-years of professional effort plus overhead. This is the daunting reality that confronts anyone who is intent on beginning to address the problem of interactions. 27,405 experiments of any kind is a labor of Hercules, even for a well-funded, fully roboticized biomedical lab.
There is a hierarchy of experimental models for studying anti-aging interventions:
Human cell cultures are the cheapest and fastest, but we learn the least
Complementing human cells are yeast cells, which actually have a life expectancy and some biology that overlaps our own
Studies of thousands of C. elegans worms can be done efficiently with robotic controls and worm counters.
Fruitflies are a great deal “more like us” than worms and they can be raised in large numbers, live just a few weeks.
Lab rats and mice are expensive, but they are mammals with biology that is much like our own. Experiments in rodent longevity last 2 to 3 years.
Human trials require extensive safety measures and typically take decades to see subtle changes in health and mortality statistics; but this is the most direct indication of what we want to know.
So, how might we begin?
We have no idea what we will find. Maybe there will be a few spectacular combinations. Maybe the interactions will turn out to be small, mostly negative, and boringly expected. (My guess is that both of these will turn out to be true.) We should not try to define the second stage of the program until we have results from the first.
The first step is to choose the most promising interventions to combine. A great number of drugs and supplements are known that extend lifespan in rodents and/or lower mortality in human epidemiology. Magalhaes and Kaeberlein have put together a large database of animal studies that seems to be off-line at present. Here is a list I proposed in this column two years ago:
Beta Lapachone (Pao d’Arco)
Dinh lang (Policias fruticosum)
Gynostemma pentaphyllum (jiao-gu-lan)
N-Acetyl Cysteine (NAC) / Glutathione and precursors
Oxytocin (not oral)
J147 (a promising new Alzheimer’s drug)
NR, NMN and NAD precursors
We might add
Polyphenols from tea
Flavinoids from blueberries
Cardarine / GW501516 / PPAR agonists
Dasatinib / Quercetin
Momordica charantia (bitter melon)
Gotu kola / Bacopa
Pine bark extract
Interventions not in pill form include
Intermittent fasting (various schedules)
Plasma transfusions from younger individuals
Transplanted young thymus
Transplanted young suprachiasmatic nucleus
How to prioritize and explore the huge number of combinations? Here are four ways we might begin to sort through the possibilities:
Use theory: Look for biochemical mechanisms that seem complementary
Traditional Chinese Medicine, Ayurvedic medicine and other ancient traditions suggest combinations of herbs that long experience says function together.
Broad screens for especially potent combinations
Statistical mining of an on-line registry of what people are taking presently
Let’s look at these one at a time.
1. Biochemical Theory
We know a few biochemical pathways that are linked to longevity. They all overlap and talk to each other. Nevertheless, we expect that treatments that address the same pathway are likely to be redundant, whereas treatments that address distinctive pathways have a better chance of synergizing. For example, insulin resistance is a robust hallmark of aging. The insulin pathway is most plastic and most accessible to intervention. Fasting and caloric restriction address the insulin pathway, as do metformin berberine, jiaogulan and bitter melon. Exercise has many benefits, some of which work through the insulin pathway.
We might continue classifying interventions that address other pathways. Here are some longevity pathways of which I am aware:
Immune senescence / thymic involution
Epigenetic reprogramming / transcription factors
Anabolism / Catabolism imbalance
P53 / Apoptosis
Someone who knows more biochemistry than I do might be willing to classify the interventions I list (and others) according to these 10 pathways (and others). Here is a template in Google Sheets, which I establish as an open Wiki. http://tinyurl.com/longevity-pathways
2. Eastern and Indigenous Medical Traditions
Many useful modern medicines are derived from ancient folk wisdom. But this work has proceeded with a deductive logic, isolating active chemicals from whole plants (as aspirin from willow bark, cycloastragenol from astragalus, and curcumin from turmeric). Many folk traditions, especially Traditional Chinese Medicine, are based on not just whole herbs but combinations of herbs that have been found over the ages to work together. Ideas may be taken from these traditions to prioritize combinations for testing. For example, the best known Chinese longevity formula is Shou-wu-chi (首乌汁;), which is compounded of (list from Wikipedia):
The Ayurvedic tradition is less contains fewer formulas, but combinations that are said to contribute to longevity include these (which I found, just for illustration, at Banyan Botanicals)
Haritaki (Terminalia chebula)
Guduchi (Tinospora cordifolia)
Amalaki (Embelica officinalis)
Kumari (Aloe barbadensis, or aloe vera)
Guggulu (Commiphora mukul)
Brahmi or gotu Kola (Centella asiatia) or closely-related Bacopa
Ashwagandha (Withania somnifera)
3. Broad screens for particularly effective combinations
Two years ago in this space, I proposed a screening protocol in which all combinations of 3 interventions from a universe of 15 would be tried on just 3 mice each. I showed with a computational model that if these included at least one lucky combination that increased longevity by more than 50%, then, despite the small number of mice, it would be identified with at least 80% confidence. Combinations of three from a universe of fifteen is a kind of sweet spot for this particular experimental design, and much less is learned if the numbers are scaled back. This means it is not feasible to test the concept on a small scale. The full proposal requires 1365 mice in cages of three, followed for at least two years. Cost estimate is about $2 million in the US or Europe, perhaps as low as $500,000 to do the same experiment in China. I would be eager to work with any lab that has the expertise and the facilities to implement this protocol. The experimental design and simulated analysis was recently published in English in a Russian journal.
4. Data-mining of an online registry where people record what supplements they are taking and commit to reporting their health history
It would be a great public service if someone were to establish a web-based registry where individuals could share information about what supplements they are taking and what results they are getting. Over years, this could turn into a data miner’s heaven for information about individual drugs and lifestyles and their interactions. The subject is too big for a controlled experiment, but enlisting the public would be a great and greatly-rewarding project.
I know there are web sites such as Longecity that are excellent resources for anecdotal accounts of others’ experiences. But the data is not in a format that lends to statistical summaries. If you know of an existing online database of this sort, please reach out and share the web address with me.
I have preliminary plans to create such a web site in conjunction with a forthcoming book project.
There may already be a viable plan for major life extension hiding in plain sight. There is no extant research program to explore the relationships and interactions among life extension measures. Eventually, some large, well-funded agency (perhaps NEA or the Buck Institute) will take on this project in a systematic way. But the large organizations are conservative, and are unlikely to begin until the ice is broken. Thus, even the first shards of information in this area are likely to be valuable indications of a new research direction.
If you have a research lab, or if you know are connected to someone who might be interested in this project, or if you have a funding source, please let us work together.
My book (with Dorion Sagan) has just been released as a Kindle edition in the UK, Australia and New Zealand, Hong Kong, Russia, Singapore and various European countries. The book is sold in America by Flatiron/Macmillan as Cracking the Aging Code. The British edition is called What Good is Death?
Life Extension Foundation has just announced that next week they are going to announce a partnership with the Young Blood Institute for what is perhaps the most ambitious human trial of anti-aging medicine ever. It’s a daring project, with what is IMO a most promising target. But I find details of their protocol puzzling, and haven’t been able to get satisfying answers from LEF or from YBI about why they’ve made the choices they have, and how they will be able to learn from the project.
The principal treatment consists in 6 plasma transfusions scheduled over 4 weeks.
Extensive testing is planned, including telomere age and methylation age in addition to a full battery of standard blood tests like lipids and inflammation markers.
The program is self-funded by research subjects, with projected cost ~ $50,000 per participant.
In each transfusion procedure, red and white blood cells will be separated and cycled back into the subject. Blood plasma with dissolved blood chemicals will be removed. It will be replaced not by full plasma from a donor but by albumin and gamma globulin only.
“Rescue Elders” project of LEF
Last year, Life Extension Foundation announced a new and ambitious program of human experimentation at the edge of medical science, sponsoring high-risk trials to prospect for anti-aging breakthroughs in the near term. (The project’s name, Society for the Rescue of our Elders, was taken from an 18th Century group in Amsterdam, Society for Recovery of Drowned Persons, that was formed after the efficacy of artificial respiration was first discovered.) Their first project was a clinical trial of rapamycin, now ongoing. This present program of plasma transfusions is their second project.
It’s my belief that the body’s primary aging clock is epigenetic. That is to say, different combinations of genes are expressed at different times in life, and in old age the constellation of genes that is turned on causes inflammation, auto-immunity, and a preponderance of anabolism over catabolism. The master’s tools are deployed in old age to dismantle the master’s house.
As a general concept, I think this is the best working hypothesis we have. But if it is correct, it doesn’t offer an immediate key to rejuvenating the body. The problem is that epigenetics is enormously complicated. (The genetic code, in contrast, is as simple as it can be—a code of correspondence between triples of nucleic bases in the DNA with the 20 amino acids that are linked together, then folded to form proteins.)
Methylation of chromosomes is the best-known and first-discovered mechnism by which genes are turned on and off. In addition to methylation, there are dozens of other epigenetic markers and signals that are applied directly to DNA or indirectly to the histone spools, beads of protein that around which DNA is coiled.
Different genes are turned on in different parts of the body. This is the primary way that the body differentiates one kind of cell from another—they all have the same genes, but different combinations of genes are turned on in a nerve cell or a muscle cell or a skin cell. Overlayed on these differences from one cell type to another, genes are turned on and off with age. This effect is reliable and consistent enough that Steve Horvath was able to construct a methylation clock based on 353 methylation sites that change consistently with age across all cell types in the body.
The connection to blood signals was supplied by research from Stanford, Berkeley and Harvard, in which blood from a young mouse is introduced into an old mouse, and is shown to rejuvenate its tissues, stimulate new growth, and promote healing. With a small conceptual leap, I imagine that there is a self-regulating epigenetic clock distributed through the body. On the one hand, epigenetic markers in each cell give each cell its characteristic age. On the other hand, these same cells are sending signals though the blood (transcription factors) that are continually updating the epigenetic program and keeping it in sync throughout the body. The hope is that (even if we don’t understand in detail how the epigenetics is programmed) the substitution of a young blood environment for an older blood environment will reprogram epigenetics in the distributed cells, and after a few cycles it will be self-sustaining. That is, once the cells are reprogrammed to be younger, they will themselves send signals into the blood that maintain the younger state.
Criticism of the protocol
Here is a description of the proposed YBI protocol. Six times over a period of 4-6 weeks, patients will be hooked up to a plasmapheresis machine. Whole blood is removed from one arm, and a mixture is returned to a vein in the other arm. The mixture that is returned will include all the patient’s own red and white blood cells. But the blood plasma, clear liquid with all the dissolved signal molecules, will be removed. The plasma will not be replaced by blood plasma from a younger patient, as in a standard plasma transfusion. Instead, the return side will contain only albumin and gamma globulin. These are the hydrostatic and immune components of the plasma (antibodies). The theory is that auto-immune aspects of aging will be addressed in this way…but the antibodies are generated continually by white blood cells, so that the treatment will not last long. Hence the rationale for frequent repetitions of the treatment, less than a week between treatments.
My principal fear is that the planned YBI protocol may be able to do only half the job. My conjecture is that it is the signal molecules that actually maintain the epigenetic program. The proposed protocol will remove the bad ones, and that’s half the job. It may be that there are transcription factors from young blood that are deficient in the old and need to be replenished. Full plasma transfusions from young donors would do both, fully replacing the blood environment of an old person with the blood environment of a young person. But it is expensive and requires many donors for each patient. It is to control expense that YBI has chosen to do do the removal, but not replacement of blood signal molecules.
Just last year, Tony Wyss-Coray headed a Stanford trial for AD, through a for-profit spinoff called Alkahest. Alzheimer’s patients were given four doses of young blood plasma. But the dose was small, a total of 1.5 liters of plasma, and the bad actors weren’t being removed. Results were disappointing, but perhaps this is because the procedure was not bold enough.
Beginning in 1924, a Soviet Bolshevik named Alexander Bogdanov experimented on himself, receiving a series of 10 blood transfusions from younger donors. He was 51 years old at the start of the experiment, and contemporaries report that he appeared physically ten years younger in the course of the procedures. He self-reported prodigious health benefits and return of youthful vigor. The experiment ended tragically in 1928, when he received blood from a student who had been infected with malaria, and died of the infection.
Harold Katcher has been thinking about the rejuvenation potential of plasma transfusions for a long while, and here is the protocol he suggested five years ago. He does not speculate about what schedule would be ideal, and he cautions us that extensive experimentation with mice and even in cell cultures would be useful before beginning human trials.
Two years ago, I spoke via skype with Jesse Karmazin (Stanford University and Ambrosia). He told me that as a med student he had done an analysis of historic data from transfusions performed at Stanford University Hospital, and found that those who had received blood from young donors had better outcomes and better long-term survival rates than those whose blood had come from older donors. I was very interested in this claim, and asked him for the data that supported it. He told me it could not be released for reasons of patient privacy. I never did get to see that data, and he never published his analysis.
Last year, a published study claimed the opposite: that in a large database of Swedish and Danish patients transfused between 1995 and 2012, they were unable to detect any survival difference between those who received blood from young donors and a matched group of patients whose transfused blood came froun old donors.
Ideally we would like to learn many details from a trial of HPE (heterochronic plasma exchange). Fundamentally, we would test the basic question whether circulating factors in the blood are indeed able to reprogram the epigenetics of cells throughout the body, and whether this will have a salubrious effect on vitality, appearance, metabolism and the immune system. A well-designed trial might also teach us more
How long does the young plasma profile remain in the bloodstream before the body’s old cells take over and drag the proportions back down to where they were? (At this point, the next infusion would be appropriate.)
How many transfusions are required before the body’s cells are reprogrammed, and the young plasma profile becomes self-sustaining?
Transfusions from young donors are a good place to start, but obviously not a practical solution for rejuvenating large numbers of people in the long term. But if we can learn which chemical constituents need to be removed and which need to be added, it is possible that a core handful of such factors might be discovered. Those that need to be added can be manufactured in bulk by vats of genetically modified E coli. Those that need to be removed can be targeted with antibodies and removed in a simplified blood filtering procedure. This is a promising research path—perhaps the most promising that is visible from where we are now. But we’ll never know if it can work until we do an expensive and time-consuming series of experiments.
How many transcription factors need to be regulated in order to the job? This is the biggest unknown. When I spoke with Irina Conboy four years ago, she was optimistic that the number may be less than ten, but last year, she was less optimistic. I take heart from the fact that just four Yamanaka factors can turn a differentiated cell into a zero-age stem cell.
Toward the future
Plasma transfusions are a safe, approved medical procedure, used for decades as treatment for (especially) auto-immune diseases. No FDA approval would be needed for a clinical trial, using transfusions “off-label” to test rejuvenation potential. However this is not a project likely to be picked up by venture capitalists looking to make a quick buck. The first reason is that the process will be expensive and time-consuming, with a great deal of trial and error. The second reason is that when it is all over, everyone will know what are the best schedules and procedures, and the most important transcription factors in our blood—but it is doubtful that this will be patentable intellectual property, or that the investors would be able to maintain a trade secret. What we need is a substantial public investment or a middle-aged billionaire angel investor who is thinking clearly about his own destiny a decade or two down the road.
Like you, dear Readers, I tend to be focused on the biochemistry, and have to remind myself again and again that the mind and body are intertwined. I came out last week with my core belief about biology: Mechanistic physics explains only half of what we are. Life has its own laws which we will discover only if we admit they exist.
In fact, the most powerful thing we can do to prolong life expectancy is to have robust connections to other humans. The best-documented effects are for empowering relationships with community (especially cooperative action for change) and intimate relations of love. Together, these factors contribute more to life expectancy than any diet or exercise program, or any supplements you can take. The difference is comparable to life expectancy difference between heavy smokers and non-smokers. (I wrote about these topics 2 years ago: [1. Social status and depression, activism vs powerlessness, 2. Family]
Elissa Epel is famous for having elucidated the connection between stress and eroding telomeres. But she has also brought us positive messages: Meditation is associated with telomerase expression and longer telomeres. Altruism breeds telomerase. Loving-kindness is associated with longer telomeres. In a publication last summer, she and co-authors documented the benefits of sex. Women (all subjects were partnered females) who had sex at least once in the week surveyed had longer telomeres than women who did not.
The result added to evidence that goes back at least 20 years. The Caerphilly study showed that frequency of sex correlated with lower all-cause mortality in men. The conclusion extends to women. The tendency of medical professionals to interpret the result in terms of the biochemistry of orgasm has been tempered, as it became clear that sex with a partner, with or without orgasm, has benefits above masturbation [ref]. Intimacy without sex has its health rewards, as does the strength of one’s community fabric.
So, in this context, the headline result from the newest study is no surprise. The puzzle is that, even though powerful connections between social relations and health are confirmed again and again, the details keep changing, and consistency is elusive.
For example, the study just cited found that subjects who reported more sexual activity had longer telomeres, but they didn’t have more telomerase activity. In fact, they had (almost statistically significant) less telomerase activity. This was a short-term study. Telomerase activity is a short-term variable, and telomere length is supposed to respond in the longer term to telomerase activity. We should not have been surprised if an increase in telomerase had been observed, without a significant difference in telomerelength. The opposite finding suggests a missing link in the causal chain. (The Discussion text in the article is very open about this mystery.)
The study included only women. Women have been found to be more sensitive to the quality of loving attention and the depth of their connections in love, while men tend to respond to the cruder quantitative variable of sexual activity [ref]. But for women in this study, telomere length was related only to the frequency of sex, and not to the quality of relationship, or to relationship satisfaction. In fact, they found no significant association with any of the subjective questions asked concerning satisfaction with the relationship, or feelings of closeness. Again, the investigators themselves were surprised.
Paradoxical results from other studies: Men (>57yo) who had frequent sex (more than once per week) and men who self-reported that sex was “extremely satisfying” had twice as many heart attacks in the ensuing five years [ref]. In the same study, results for women were not strong enough to be statistically significant, but were strange enough to be puzzling. Women (>57yo) who reported sexual relations that were highly satisfying had higher risk of cardiovascular disease, but women who reported most intense pleasure from sex had lower risk. “These findings challenge the assumption that sex brings uniform health benefits to everyone.”
This classic study found that marriage offers substantial benefits in life expectancy for both men and women, but that the benfits for men are far larger. The relative risk in mortality rate, unmarried vs married, is 1.5 for women but 3.5 for men. The large disparity has not held up in more recent studies.
This is the most comprehensive recent review of the relationship between social variables and all-cause mortality, but it is confusingly written (I believe the verbal interpretation of statistics is incorrect). The message comes through loud and strong, that social integration accounts for a large benefit in decreased all-cause mortality, accounting for 5 to 10 years of life expectancy. But even more than in other fields of social science, there are contradictory results and inconsistencies that thwart anyone trying to tell a neat story.
Why is social connection so important to health
“Two main types of models have been proposed to explain how social support influences physical health. In main-effect models, high levels of social integration are health promoting, regardless of whether one is under stress [ref, ref]. Greater integration into one’s social network gives an individual identity, purpose, and control, a perceived sense of security and embeddedness, and a source of reinforcement for health-promoting behaviors or punishment for health-compromising behaviors, all of which can promote health [ref]. In the stress-buffering model [ref], the negative effects of stress occurring outside of one’s social relationships (e.g., at work) are diminished by the presence of strong social support, which can mitigate stressful events directly (e.g., intervening on a friend’s behalf) or through reducing stress appraisals [ref].” [quoted from Robles, 2004]
Bert Uchino distinguishes between “perceived support” and “received support”. The correlation of the former with health and mortality variables is robust. But the latter is sometimes found to be inversely correlated with health. This seems to say that if people are helping you and you don’t appreciate it, you’re worse off than if you had been on your own. If you think you’re embedded in a caring and supportive community, you’ll live longer. If you’re actually embedded in a caring community, but you devalue what you’ve got or if you isolate yourself because you’re more comfortable that way, your life expectancy is shortened. This is a morality tale if I ever heard one.
Conflictual interactions in the context of marriage (as in Western culture generally) contribute to higher levels of systemic inflammation [ref]. But this study found no relationship between job stress in men and measures of chronic inflammation. Maybe it depends on what is meant by “stress”. This study suggests that feeling out of control (powerlessness, low status) is associated with markers of inflammation.
Why do we care about this? Many of us are fanatical about following the best evidence when designing exercise and supplement regimens for ourselves. But is there anyone out there who is waiting for the latest correlation with telomere length before deciding whether to fall in love? (I didn’t think so.)
No, the reason we care about this subject is that it reminds us that aging is a social process almost as much as it is a biological process, even if the social correlates of longevity confound our best intuitions about how to live well.
And perhaps it reminds us, indirectly, that in the “rationalization” of our health care system, we have made a bad bargain. Over the course of my lifetime, medical practice in America has gone from a model of individualized care by family doctors to impersonal care by specialists. Medical care has become more evidence-based, and there is a much better chance that the doctor who treats your condition has a deep knowledge and experience of that condition. But what we’ve lost along the way is the doctor-patient relationship—both because you see a different specialist for each condition, and also because as doctors’ time is squeezed to optimize profit, the time for listening and empathizing has been eliminated. Despite the accumulation of studies showing that doctor-patient relationship has an outsized effect on prognosis, our present health care system is systemically deficient in human caring.
This time each year, I take the liberty of posting something more speculative and personal. In this essay, I propose that everything we consider the “scientific world-view” is only half the story, and that science must expand its foundations if it aspires to be a complete account of reality.
A reductionist approach to science has become so ubiquitous that many scientists find it difficult to imagine that science can be done in any other way. Interactions among elemetary particles are the ultimate explanation, the only final cause. Biology can be reduced to chemistry. Chemistry is the science of large numbers of atoms, interacting according to the laws of quantum physics.
But reductionism is only a habit of the way we do science. It is logically possible that there are global laws, interconnections, entanglements; and that these are discoverable by investigation that is rigorously scientific . Teleology is commonly dismissed as “unscientific”, but it is precisely teleology that we may need to explain a host of diverse findings that conventional science has swept beneath the carpet.
Camille Flammarion 1888 copy of 16th Century woodcut. Bettman Archive calls it “Man Looking into Outer Space” Original artist unknown.
One of my oldest friends is a professor of computer science at a great mid-western university. An Israeli-American, Uri is descended on his mother’s side from an ancient line of Kabbalist mystics, but his philosophy is strictly materialist. He believes that “the mind is what the brain does”, that the brain is a computer, and that electronic computers can be programmed to do anything that our brains can do. Like a great majority of computer scientists, he believes that subjective consciousness is something that arises when computation attains a certain kind of complexity.
Last summer, Uri told me a story from his youth. In college, he had dated a young woman, a passionate political activist. Years after he had lost touch with her, she sunk into depression with the election of Ronald Reagan. Uri awoke one night, sweating and screaming, from a nightmare in which she had jumped from a building. Though he had not talked to her in several years, he reached out and tried to contact her the next morning, and her parents informed him she had killed herself that very night, jumping from the window of her apartment. Uri was shaken at the time, but he has filed the experience in his memory as a coincidence, a curious anecdote with no particular message about the way our world works.
Sitting in a canoe, listening to Uri’s story, I asked him if he thought an artificial intelligence might ever have such dreams. What would he think if his story and many like it were collected in a stastical database, and it could be demonstrated that such “coincidences” were far too frequent do be dismissed, that their composite probability was far rarer than “five sigma” (roughly “one chance in a million”), which is a conventional threshold for announcing that physics has discovered a new particle. He responded thoughtfully: He didn’t have time to do that kind of analysis. It depends on so many people’s stories, and people’s memories of such things aren’t so reliable. But if it could be established, he said, he would be forced to conclude there were new sub-atomic forces that brains can use to communicate, and that physics had not yet discovered. In any case, he was committed to the idea that reality is physical — space, time, matter and nothing else — and that every phenomenon of nature must be explainable in reductionist terms. By definition.
How Science came to be narrow-minded, with universal ambitious
Don’t doubt the Creator, because it is inconceivable that accidents alone could be the controller of this universe.
— Isaac Newton
Newton’s scientific ambition was prodigious. He first conceived the idea that the universe was governed by precise mathematical laws that were independent of place and time. But he never imagined that physics was a complete picture of the world. It was only in the 19th Century that the idea took hold that physical law might explain everything. Science had been enormously successful in accounting for diverse phenomena, expanding again and again to explain more of our world. Then scientific philosophy made an audacious leap: Every phenomenon in our universe is regular. All of our experience can be accounted for in terms of deterministic mathematical laws.
Is this statement true? We all assume it is. But in fact, it is an empirical statement, a bold one, to be sure, and all the more reason it should be challenged and tested experimentally.
Of course, it’s not literally true that two experimenters doing the same experiment always find the same result. There’s experimental error—mistakes and misjudgments that enter any human enterprise. And in biology, there is the complication that no two organisms are exactly alike. These things were understood and accounted for in the Nineteenth Century. This was the time when “vitalism” was stripped out of biology, and living things were boldly assumed to depend on the same mechanistic laws as non-living matter. Biology was conceived to be built upon chemistry, and chemistry could be understood as the interactions of atoms. It was at the level of atomic physics that the Universal Machine operated in a manner precisely determined by mathematical laws.
But 20th Century science shattered determinism. The Scientific World-view retreated just far enough to allow for quantum randomness and the Heisenberg Uncertainty Principle.
“Philosophers have said that if the same circumstances don’t always produce the same results, predictions are impossible and science will collapse. Here is a circumstance that produces different results: identical photons are coming down in the same direction to the same piece of glass. We cannot predict whether a given photon will arrive at A or B. All we can predict is that out of 100 photons that come down, an average of 4 will be reflected by the front surface. Does this mean that physics, a science of great exactitude, has been reduced to calculating only the probability of an event, and not predicting exactly what will happen? Yes. That’s a retreat, but that’s the way it is: Nature permits us to calculate only probabilities. Yet science has not collapsed.”
— Richard Feynman
To Einstein’s consternation, God does play dice with the world. When the Twentieth Century discovered quantum indeterminacy, most philosophers of science made the minimal modification to their deterministic picture. To them, the future state of the universe is determined by its present state plus pure chance. In this paradigm, there is nothing outside physics, or if there is such a thing as “soul” or “spirit” or “free will”, it is irrelevant to science and to experience. It can have no observable effects, because the physical universe is a closed system, governed perfectly by a combination of deterministic laws and pure chance.
This is the philosophy of “materialism” or “physicalism” that has become synonymous with the scientific world-view today. But it is far more explicit than the original scientific world-view, which says only that our knowledge of the world depends on empirical observation plus mathematical logic. In fact, the original scientific world-view is a system for discovering truth, but it is silent about what that truth ought to be. This expanded scientific world-view is not just a statement about methods, but contains a description of the nature of the world. It is a scientific theory, in the sense that it says something about the empirical nature of reality. Like all scientific theories, the expanded scientific world-view can never be proven true, but it can be falsified by observation.
The original scientific world-view as bequeathed to us by the Enlightenment is an epistomology which we can accept or reject, but no arguments can be adduced for or against it. The expanded scientific world-view is a statement about the world, and we may legitimately ask, “Is it true?”
The issue of reproducibility is the crux of the matter, and it is related to science in two ways.
On the one hand, science seems to depend on reproducibility, at least in the statistical sense. If different experimenters at different times and places get different results from the same experiment, how can we ever hope to come to agreement about the world we live in? Reproducibility—in the expanded, statistical sense—seems to be a necessary feature of the world if we are to be able to study the world with science.
On the other hand, we may treat reproducibility as an empirical question. Is it true that the same experiment always results in the same results, at least statistically? To rephrase more provocatively: Is it true that the universe is governed by scientific laws that always hold true, or are there exceptions and one-off happenings, things that occur sometimes but without a regularity we can codify?
We might ask, “are miracles real?” Should the scientific world-view take a firm stance on this issue and answer, “No!”? Or should science be open-minded, and consider the possibility that those who report miracles are not always deluded or mistaken?
Evidence that we need a new model
From one stage of our being to the next
We pass unconscious o’er a slender bridge,
The momentary work of unseen hands,
Which crumbles down behind us; looking back,
We see the other shore, the gulf between,
And, marvelling how we won to where we stand,
Content ourselves to call the builder Chance.
— James Russell Lowell
There is no shortage of credible reports that cannot be explained by the reductionist paradigm of science, but most have been shunted out of the mainstream journals, attacked or simply ignored.
Perhaps you have had a dream or premonition similar to Uri’s. If not, you probably know someone who has. It has become common for scientists to dismiss “anecdotal evidence” without feeling a need to explain it. This comes from a ubiquitous assumption that all experiments are replicable — exactly the assumption which I think we need to challenge.
Daryl Bem is an emeritus professor in the Cornell Psychology Dept, recently retired after a long and distinguished career doing mainstream research about stimulus and response. In one of his last publications, he broke into a well-regarded psychological journal with an article that documented responses in human subjects that preceded the stimulus. This is precognition. The subject’s subconscious knew or sensed what image was about to appear before him on a computer screen. Julia Mossbridge summarized a substantial body of research, which collectively corroborates the reality of precognition with 99.999999999% certainty.
Robert Jahn, retired dean of the engineering school at Princeton University stumbled (through his student’s term project) upon evidence for the ability of human intention to affect probabilities that ought to be “quantum random”. Jahn had the curiosity to investigate further. When the anomaly wouldn’t go away, he refined the experiment and collected data over 30 years, by which time his results had achieved 5-sigma statistical significance — on a par with evidence for the Higgs Boson. Jahn was ostracized and ridiculed, and colleagues began to discredit his work in aerospace engineering based on his willingness to openly consider the possibility that the human mind might be able to affect quantum processes outside the organism.
Dean Radin has conducted a broad array of experiments that demonstrate different aspects of telepathy, precognition and telekinesis. He has a background in physics, and routinely takes extraordinary measures to guarantee the isolation of his experiments from extraneous physical influences. In one recent project, he found that focused attention of a person who is not in physical contact with the equipment can shift interference fringes of laser light passing through two slits. This connection between thought and quantum is akin to results reported by Jahn.
Outside the world of parapsychology, there are uncontroversial animal behaviors that defy explanation. Fish, turtles and cetaceans routinely navigate thousands of miles through the ocean, their guidance system unknown to science. Each fall, a generation of Monarch butterflies is able to retrace the 2,000-mile migration path flown by their great, great, great grandparents six months earlier. Flatworms have been conditioned to respond to light, then they are ground up and fed to other flatworms, who acquire some of the conditioning through cannibalism [skeptic’s account].
Dozens of labs around the world have successfully replicated the cold fusion experiments of Pons and Fleischmann. Reports of their work are sequestered in this on-line journal because mainstream physics journals have declared that cold fusion is impossible. In fact, there is nothing in fundamental physics that precludes cold fusion; it is, after all, a highly exothermic reaction, and the energy release is exactly as predicted. But cold fusion implies a new bulk quantum effect (akin to superconductivity, superfluidity and lasers) for which there is yet no theory. [video summary] The physicist who taught me quantum mechanics at Harvard was a Nobel laureate who became irate when the American Physical Society refused to publish his proto-theory of cold fusion.
Ian Stevenson and Jim Tucker are medical doctors who have each spent decades investigating cases “suggestive of reincarnation”. Children recall past lives, with details about the circumstances of that life that are later corroborated. Stevenson noted the frequent presence of birthmarks where former selves suffered trauma at death. Helen Wambach and Carol Bowman have used hypnosis to help adults find access to information about past lives.
The ganzfeld protocol is the most reliable experimental procedure for demonstrating telepathy. A meta-analysis of 59 ganzfeld studies reports a combined success rate of 30% in identifying a target photograph when the chance hit rate should be 1 in 4. The improbability of this result has been calculated in different ways, with results from 10-12 to 10-8.
Through a glass darkly: Where post-reductionist science is headed
All the progress in science since the Enlightenment has built on a reductionist paradigm: breaking down the whole into parts, explaining the parts in terms of influences that are nearby in time and space. If this is not the whole story, then we might imagine there are relationships among distant events. There might be large-scale patterns that cannot be explained as “emergent” from local laws. There may relationships that appear to us as retrocausality. There might be destiny.
It is clear to me that what physics calls “quantum random” is not random at all, but rather is determined non-locally, via quantum entanglement. Events distant in time and space are linked in a manner that baffle our usual methods of scientific inquiry, but that may be discoverable by a new kind of science.
There is nothing un-scientific about such a hypothesis, and in fact quantum mechanical “entanglement” suggests that such patterns must exist. David Bohm has laid foundations for a science based on holistic patterns in an Undivided Universe. He offers us a beginning toward understanding an “implicate order” that may complement the explicit order in time and space that is the basis of all of mainstream physics.
The Constellation, by Joan Miro
Possibly related is the idea that mind has an existence separate from matter, that free will operates in a sphere that is able to influence matter on a quantum level. This could be a resolution in Cartesian dualism of David Chalmers’s hard problem. One link between the realm of the self outside of space and time and the realm of physical matter could be through the quantum mechanics of the brain. Roger Penrose and Stuart Hameroff have proposed a model. Stuart Kauffman cites evidence that neurotransmitters in the brain are poised on a quantum knife edge where their behavior is dictated either by randomness (in the conventional view) or could this be the portal by which intention enters into physical behavior?
It may turn out that life is not an opportunistic parasite in a vast, cold and meaningless cosmos. Life may be built into the laws of physics at the very foundation. It may be that living behaviors are woven into the fabric of the cosmos. Or it may be that awareness and free will live in a realm separate from time and space, but linked to physics at the quantum level. This would be a way to resolve the Anthropic Coincidences without resort to an embarrassment of universes.
These ideas are not un-scientific, but they are difficult to study with current scientific methods. At the dawn of the Twenty-first Century, experimental science is bursting at the seams with phenomena crying out for an expanded scientific paradigm. The crisis will not be resolved by keeping speculative science out of the mainstream journals. It is not likely to be settled by a brilliant guess about the nature of reality that resolves all our anomalies in one fell swoop. The only way forward is for science to expand its methods and entertain a broad array of wild, new ideas, most of which are bound to fail. But if we open the gates to speculative ideas, if we shake off taboos about teleology and holism, if we broaden the scope of experiments and our ways of understanding them…then I trust that our collective brainpower will be up to the task of formulating a picture of the world that comprehends a greatly expanded — dare I say “wondrous” — vision of our world.
In 1999, I met Cynthia Kenyon for the first time, and she told me her one-line proof that aging is an evolved trait. Lifespans in nature range from hours to thousands of years. This shows that natural selection is not constrained, but can implement aging on whatever time scale is appropriate.
A few years ago, Annette Baudisch added another dimension to this proof: It’s not only the duration of life, but the shape of the aging curve that takes on so many various forms. Misguided theories of aging are based on the human life cycle (and others like it) with Gompertz mortality. (In the 19th Century, Benjamin Gompertz first noted that risk of death increases exponentially with age.) Several smart theorists have been seduced into attempting proofs—either from thermodynamics or from evolution—that gradual aging is a necessary consequence of the conditions of life.
But Baudisch gathered data on hundreds of animals and plants, demonstrating that the exponential shape of the human mortality curve is just one among many possible. Furthermore, every conceivable shape is paired with every time scale. Any theory of aging must account for all these ways to age. Or not to age: Baudisch got her start in research collecting examples of negative senescence. Given this variety, the only viable theory is, “nature can do whatever she wants”. More formally, natural selection can mold aging as appropriate to fit every possible niche in every ecology.
Aging is ancient, but it is not universal. We are accustomed to think that animals age gradually beginning at maturity, ending with inevitable death, but life is stranger than this. Some animals and many plants have escaped from aging entirely. Many more pass through long periods of their lives without aging. Cicada nymphs mature underground for seventeen years, while not being subject to increasing death rates or aging in any other sense. Then the cicada emerges, mates, ages and dies all in a single day. This is a dramatic example of semelparity, in which aging occurs all in a rush after a single burst of reproduction. In many such cases, the aging can be experimentally decoupled from the reproduction, demonstrating once again that the aging is a separate adaptation. The simplest example of this is the pansies in your garden. As long as you snip off the flowers before they go to seed, you can keep the plant blooming all summer.
Snipping off flowers before they go to seed will keep the plant alive all summer.
A few animals and many plants don’t age at all, but grow larger and stronger and more fertile through their entire lifespans. Some have been observed to regress from mature states, and start life anew as larvae, with a full life expectancy ahead of them.
What does life without aging look like?
Sanicula is a shrub growing in the meadows of Sweden, and one plot in particular has been studied continuously for seventy years. Sanicula has a life expectancy comparable to a human, but sanicula does not age. For people, the probability of dying gets higher with each passing year, whereas for sanicula, about one shrub in 75 dies each year, irrespective of age. A 75-year-old plant has no more mortality risk than a 10-year-old plant. For a person, the life expectancy at birth might be 75 years; the life expectancy for someone 60 years of age might be 18 more years, and for someone 80 years old, perhaps the life expectancy is 7 more years. For a sanicula, the life expectancy of a seedling is 75 years, and the life expectancy of a 60-year-old shrub is 75 more years. There are, in fact, a few 200-year-old saniculas, and they have a life expectancy of 75 more years. At this rate, about one plant in a million should live a thousand years. A thousand-year-old sanicula is no closer to death than a sapling.
It is unknown today whether lobsters age or not. Lobsters are fished so heavily that they rarely grow larger than a pound, but lobsters weighing more than 5 lbs are still caught occasionally (and usually released). The largest lobster on record was 44 lbs. The reason that the large lobsters are released back into the ocean is not just that they won’t fit on a dinner plate. Lobsters become more fertile as they grow larger, and their young are more viable. A few large lobsters can be the breeding stock for a large area. We don’t have an age record for the oldest lobster ever caught because lobsters don’t have annual rings or layers that broadcast their age. The 44-lb animal was said to be more than one hundred years old, but no one knows for sure.
…and not the largest on record, either.
Clams also can grow larger and more fertile indefinitely. But clams have growth rings that count the years for us. The oldest clam on record (an ocean quahog of the species Arctica islandica) has been tagged at 507 years. Small clams have natural predators, including starfish that latch onto their shells and pull them apart by brute force. But once a clam outgrows the arms of a starfish, it can keep growing indefinitely. Clams have one foot, one mouth, no eyes or ears or stomach, no brain. Giant clams, up to 800 lbs, live the same lifestyle as their smaller relatives, sucking in the seawater, taking in thirty thousand times their weight in water every day, and filtering out plankton and algae, which continue to grow and reproduce inside them. Like giant lobsters, the giant clams provide eggs for a whole community. They have been known to release half a billion eggs in a day.
Giant clams can live hundreds of years.
All of the longest-living species in the world are trees. There are several reasons for this. Trees invest a great deal in growth, always trying to project their leaves upward, out of the shade of other trees, to compete for the best light. The oldest trees tower above the forest, and get first dibs at the sun’s energy. So there is a powerful evolutionary incentive for trees to live a long time so they can grow taller than their competitors, and the sky is the limit.
As opposed to plants, animals’ life spans are limited by a requirement of ecological stability. Most plants produce their own food, but all animals depend on other species (either animals or plants) for their food. Hence it is natural for a plant to live as long as possible and make as many seeds as it can make. Trees are the best examples of Darwin’s dictate that life is about reproduction. (Sequoia trees can produce more than a billion seeds.) But animals can’t get away with reproducing faster than the plants at the base of the food chain. Animals are evolved to guard the species lower down on the food chain, and they must never reproduces faster than the animals they eat—otherwise, in a very few generations, they will wipe out their food source and their children will starve.
Do trees age at all? Some do, and some don’t. Most trees go for long periods of time growing ever larger and less vulnerable to death. That counts as negative senescence. Of course, size itself becomes a hazard as a tree becomes the tallest in its grove—the first to be struck by lightning, the most top-heavy and vulnerable to toppling in the wind when erosion weakens the roots’ hold on terra firma. But in addition to this, it seems that most trees have a characteristic age, after which death finally becomes more likely with each passing year. There is some indication that trees become more vulnerable to fungus and disease with old age, but for the most part, old trees succumb to the mechanical hazards of excess size. The very ability to continue growing that offers them the possibility of “reverse aging” over so many decades proves in the end to be their downfall.
Instant Ageing; Sudden Death
Semelparous animals and plants reproduce just once in a lifetime, usually followed promptly by death. Sudden post-reproductive death is common in nature, affecting organisms as varied as mayflies, octopuses, and salmon, not to mention thousands of annual flowering plants.
The cause of death in semelparous organisms varies widely. Theorists once assumed that the animal just wears itself out in a burst of reproductive effort, but this idea has not held up. The burst of reproduction and the sudden death seem to be separable and independent adaptations. In addition to the example of pansies mentioned above, octopuses can be induced to live beyond their burst of reproduction if their optic gland is surgically removed; and Atlantic salmon, close cousins of the Pacific salmon, also endure treacherous migrations upstream in order to mate, but they don’t necessarily die after laying eggs, and can return to the ocean for another bite at the apple.
Chinook salmon hatch in river pools, often hundreds of miles upstream from the sea. They spend their first year or two in the protected environment of the river, where life is tamer and larger predators rarer. When they have grown large enough to compete, they migrate downriver, out to the ocean to seek their fortunes. They may range up to 2,500 miles from the mouth of the stream where they first entered the sea. They live in the ocean anywhere from two to seven years, growing larger but not weakening or becoming frail with age. When they are ready to reproduce, they find their way back, not to any handy river mouth but to the very same river pool where they were hatched. Their journey is a headlong rush, simultaneously into fertility and death.
Salmon fight rushing water to return to their spawning ground.
By the time the adult salmon reach their spawning ground, their metabolisms are in terminal collapse. Their adrenal glands are pumping out steroids (glucocorticoids) that cause accelerated—almost instant—aging. They’ve stopped eating. Moreover, the steroids have caused their immune systems to collapse, so their bodies are covered with fungal infections. Kidneys atrophy, while the adjacent cells (called interregnal cells, associated with the steroids) become greatly enlarged. The circulatory systems of the rapidly deteriorating fish are also affected. Their arteries develop lesions that, interestingly, appear akin to those responsible for heart disease in ageing humans. The swim upstream is arduous, but it is not the mechanical beating that fatally damages their bodies. It is rather a cascade of nasty biochemical changes, genetically timed to follow on the heels of spawning. The symptoms affect both males and females, despite the uneven share of metabolic work that falls to females, whose eggs may constitute a third of their body mass during the final leg of their trip.
Some organisms are genetically programmed not to eat after reproduction and starve as a result; it’s quicker and surer than traditional ageing. Mayflies entering adulthood have no mouth or digestive system whatever. Elephants chomp and grind so many stalks and leaves during a lifetime that they wear out six full sets of molars. But when the sixth set is gone, they won’t grow another, so old elephants can starve to death.
Elephant molars get a lot of wear. The elephant can replace them 5 times but not 6.
Praying mantis males take the prize for the most bizarre and macabre mode of programmed death. After an elaborate mating ritual, the male fertilizes his mate’s eggs with his bottom half, while the female chomps off his top half. Sometimes.
Praying Mantis Love is Waaay Weirder Than You Think | Deep Look - YouTube
Octopuses makes an especially good story. They live a short time, a few months to a few years, depending on the species, and they die after reproducing once. After mating, the female guards and cares for her eggs, but if conditions are not right for her brood, she may eat them, and then she has another chance to try again later. Like praying mantisses, the octopus female sometimes cannibalizes the male. If she decides the time is right to deliver her young, not only does she refrain from eating her eggs, she stops eating altogether. The octopus mom guards her eggs from predators, focused and immobile for months on end. (They are such smart animals, even playful. How is it that they don’t get bored?) During this time, her mouth seals over. She may live for years in this state of suspended animation, just guarding her eggs; but when the eggs hatch, she dies within a few days. Her death isn’t from starvation. We know because there are two endocrine glands, called “optic glands” though they are unrelated to the eyes, whose secretions control mating behaviour, maternal care, and death. The optic glands can be surgically removed, and the octopus mom lives longer. If just one optic gland is removed, the female doesn’t eat but still lives an extra six weeks. If both optic glands are removed, then the octopus doesn’t lose her mouth and resumes eating after the eggs hatch. She then regains strength and size and can live up to forty weeks more.
In 2007, Bruce Robison of the Monterey Bay Aquarium Research Institute discovered a deep-sea octopus mom watching over her clutch of 160 eggs in the deep, cold waters off the California coast. He returned periodically to observe the same octopus on the same rock in the same position. From 2007 to 2011, she didn’t eat, and she didn’t move except to slowly circulate the water over the eggs, assuring a fresh supply of mineral nutrients. After four and a half years, the eggs hatched, and the octopus mom disappeared, presumed dead, all within a few days. The empty eggshells were observed, memorializing her effort. It was the longest gestation ever observed.
olga the Giant Pacific Octopus tends to eggs - YouTube
Ageing in Reverse
In 1905, the Dutch biologist Friederich Stoppenbrink was studying the life cycles of Planaria, a kind of flatworm, a fraction of an inch long, common in freshwater ponds. He noted that when the animals didn’t have enough to eat, they systematically consumed themselves, beginning with the most expendable organs (sex), proceeding to the digestive system (not much use in a famine), and then muscles. The worms got smaller and smaller until the most precious part—the brain and nerve cells—were all that remained. Stoppenbrink reported that when he started to feed the worms again, they grew back, rapidly regenerating everything they had lost. What’s more, they looked and acted like young worms, and when their cohorts who had not been starved began to die of old age, the starved-and-regrown worms were still alive and kicking. This trick could be performed again and again. As long as Stoppenbrink kept starving and refeeding the worms, they went on living without apparent signs of age.
The medusoid Turritopsis nutricula achieved its fifteen minutes of fame when it was hailed as “the immortal jellyfish” in science news articles of 2010. The adult Turritopsis has inherited a neat trick: after spawning its polyps, it regresses back to a polyp, beginning its life anew. This is accomplished by turning adult cells back into stem cells, going against the usual developmental direction from stem cells to differentiated cells—in essence driving backward down a one-way developmental street. Headlines called Turritopsis the “Benjamin Button of the Sea.” Here again, life seems to imitate art.
Turritopsis can regress and begin life anew
Carrion beetles (Trogoderma glabrum) perform a similar trick, but only when starved. As they play life out on a carcass in the woods, the beetles go through six different larval stages in succession, looking like a grub, and then a millipede, and then a water glider before ending up as a six-legged beetle. A pair of entomologists working at the University of Wisconsin in 1972 isolated the sixth-stage larvae (when they were just ready to become adults) in test tubes and discovered that without food, they regressed to stage-five larvae. If they were deprived of food for many days, they would actually shrink and regress backward through the stages until they looked like newly hatched maggots. Then, if feeding was resumed, they would go forward again through the developmental stages and become adults with normal life spans. They found they were able to repeat the cycle over and over again, allowing them to grow to stage six and then starving them back down to stage one, thereby extending their life spans from eight weeks to more than two years.
Carrion beetle, when starved, reverts to any of its previous larval stages.
Hydras are radially symmetrical invertebrates, each with a mouth on a stalk, surrounded by tentacles, which grow back when cut off—like the many-headed monster of Greek mythology for which they are named. With their tentacles, they snare “water fleas” and other tiny crustaceans, on which they feed. Some hydras are green, fed by symbiotic algae living beneath their translucent skin.Hydras have been studied for four years at a time, starting with specimens of various ages collected in the wild, and they don’t seem to die on their own or to become more vulnerable to predators or disease. In the human body, certain cells, such as blood cells, skin, and those of the stomach lining, slough off and regenerate continuously. The hydra’s whole body is like this, regenerating itself from stem cell bedrock every few days. Some cells slough off and die; others, when large enough, grow into hydra clones that bud from the stalk-body to strike out on their own. This is an ancient style of reproduction, making do without sex. For the hydra, sex is optional—an occasional indulgence.
One recent article claims that the hydra does indeed grow older, and it shows it by slowing its rate of cloning. The author suggests that perhaps clones inherit their parents’ age. The hypothesis is that only sexual reproduction resets the ageing clock. If this is true, then the hydra’s style of ageing is a throwback to protists, ancestral microbes more complex than bacteria. Amoebas and microbes of the genus Paramecium are examples of these protists, single cells in a vast lineage that has anciently radiated into over one hundred thousand species and includes all the seaweeds, slime moulds, and ciliates and other organisms that do not belong to the animal, fungal, plant, or bacteria kingdoms.
For paramecium, sex and reproduction are two entirely different functions. Reproduction takes place by simple mitosis—the cell clones itself. Sex takes place by “conjugation”. The paramecium sidles up to another paramecium, their two cells merge and then the two cell nuclei merge, mixing their DNA, reshuffling within each chromosome, as genes cross over from one to the other. Then the two cells separate, but the two cells that come apart are not the two cells that entered. Each one is a different combination of the two original cells—“half me and half you.”
Here is the connection to aging: Cells keep track of how many times they have cloned themselves via telomere length. Each time the cell clones itself, the telomeres becomes a little shorter. When it becomes too short, the cell languishes and dies. The telomere can be re-set to full length with the enzyme telomerase, but this only happens during conjugation, not during mitosis. The result of withholding telomerase is that the individual can clone itself about a hundred times, but at some point, it must share its genes via conjugation, giving up its individual identity. Telomere shortening is an ancient mode of aging that forces the individual to share genes with the community.
This ancient process was a template for the future evolution of aging. Many higher organisms have telomeres that shorten through our lifetimes, until we die. Telomerase is held back in humans, dogs and horses, but not pigs, mice or cows. In the former animals, telomeres are only reset during reproduction, when a new individual is formed from gamete cells of two different parents. Just like paramecia.
Bees That Can Turn Ageing Off
Queen bees and worker bees have the same genes but very different life spans. In the case of the queen bee, royal jelly switches off ageing. When a new hive begins, nurse bees select—arbitrarily so far as we can tell—one larva to be feted with the liquid diet of royalty. Some physiologically active chemical ambrosia in the royal jelly triggers the lucky bee to grow into a queen instead of a worker. The royal jelly confers upon the queen the overdeveloped gonads that give her a distinctive size and shape. The queen makes one flight at the beginning of her career, during which she might mate with a dozen different drones, storing their sperm for years to come.
Weighted down with eggs and too heavy to fly, the full-grown queen becomes a reproducing machine: she lays at a prodigious rate of about two thousand per day, more than her entire body weight. Of course, such reproductive regality requires a suite of specialized workers to feed her, remove her waste, and transmit her pheromones (chemical signals) to the rest..
Were I, like Adam, choiced by evil snake
That fruit of knowledge I might free partake
Or, spurning insight, might forever be,
And dwell in vast, obscure eternity…
By two such options I’d be sorely torn—
’Twas not for blind submission I was born.
Infinity sans knowledge is no prize,
While light that fades to black before mine eyes
Is destiny no man would freely choose,
For what we have is all we have to lose.
Posed thus, ’tis plain: rebellion is my path—
I’ll risk the flaming ire of God’s own wrath,
His knowledge, freely giv’n is not so dear
As what by our own efforts we make clear.
With tools of science I’ll investigate
The logic of this world and mine own fate;
While passions I will equally devote
To quest for health, and death’s own antidote.
— Josh Mitteldorf
Detail from The Last Judgment by Heironymus Bosch (1450-1516)
“The way evolution works makes it impossible for us to possess genes that are specifically designed to cause physiological decline with age or to control how long we live.” —from a Scientific American article by Jay Oshansky, Bruce Carnes, and Leonard Hayflick (2004)
Most biologists still think this way, even among people who study aging, even those working on anti-aging medicine. If you believe this as a matter of bedrock theory, then what do you say when a gene is discovered that cuts life short, but still manages to dominate the gene pool? You say that the gene has benefits that outweigh its costs. It is a fertility gene, but it has side effects that kill you slowly. Or it has survival benefit in the wild that are difficult to study in the laboratory. This is called the theory of antagonistic pleiotropy. “Pleiotropy” is the biological term describing a situation where one gene has two or more effects on the phenotype. In 1910 when the term was invented, this was thought to be a special situation, requiring a special name. We now know that almost all genes have multiple effects.
In theories of aging, antagonistic pleiotropy (in different variants), is considered the unassailable king of the roost. It is not questioned. There is no such thing as an aging gene, so as more and more aging genes are discovered, they carve out more and more excuses and exceptions to preserve their bedrock evolutionary theory. Just this week, there are two new examples, in worms and in people.
The First Aging Genes
In the 1980s, Tom Johnson, working at UC-Irvine, was studying aging in the lab worm C. elegans. Johnson grew worms with a defective gene, which he named age-1 after he discovered that worms without it lived half again as long as normal worms. No one had ever imagined that a single gene could have such an effect on life span. In fact, the best experts in evolution had theorized that “everything ought to wear out at once,” so that no single gene could have any noticeable effect. Johnson’s discovery was the more remarkable because longer life required nothing new but rather the deletion of an existing gene. This implied that the effect of the age-1 gene was to cut the worm’s life short. What was it doing in the genome? How did it get there? And why did natural selection put up with it?
Johnson had a ready explanation. He believed (and still believes, I believe) in antagonistic pleiotropy. The worms without age-1 laid only a quarter as many eggs as other worms. It was easy to see how they had been losers in Darwin’s struggle. In fact, Johnson’s finding looked like a dramatic confirmation of the theory that aging was a side effect of genes for greater fertility, greater individual fitness. Aging had not evolved directly, selected for its own sake, but as a cost of greater fertility, a real-life example of antagonistic pleiotropy.
But a few years later, this story unraveled, and what had been confirmation of theory became a direct contradiction. Johnson discovered that his mutant worms actually had two genes that were different. In addition to age-1, there was another, unrelated gene defect (fer-15) on a separate chromosome. By crossbreeding, he was able to separate the two. Worms with the fer-15 mutation had impaired fertility without extended life spans. Worms with the age-1 mutation had extended life spans with unimpaired fertility. This was a full- fledged Darwinian paradox: the age-1 gene found in nature was the one that gave the worm a short life span. It was the “defective” gene that caused the worm to live longer. Age-1 looked not like a selfish gene but an aging gene. It was just the kind of gene that natural selection ought to eliminate handily. How had this gene survived, and what was it doing in the worm genome?
Age-1 was only the first case of an aging gene in worms. There are now hundreds of genes known that lengthen life span when they are deleted. In other words, these genes, when present, have the effect of shortening life span. Some of them tend to improve fertility; some don’t. Some have other beneficial side effects, but about half the known life-shortening genes offer nothing in return, or at least nothing that has yet been identified.
Still, the pleiotropic theory is rarely questioned.
Fertility in male worms
A recent Nature paper from the Shanghai laboratory of Shi-Qing Cai identifies a pair of C. elegans genes that affect the span of fertility in males. The group collected worms from many different locations around the world. They found that in some worms, the males remain fertile almost their entire lives, while other males undergo rapid reproductive senescence. With some excellent detective work, using database searches and genetic manipulation that would have been impossible a few years ago, they identified the genes rgba-1 and npr-28. Each exist in two versions in wild populations, even though they have powerful effects on reproductive fitness. Evolutionary theory tells us that genes with a close relationship to fitness should be subject to strong selection, so that the high-fitness version should promptly wipe out the low-fitness version. In accord with theory, the authors cite statistical evidence that the high-fitness version of npr-28 has recently displaced the low-fitness version. But, paradoxically, the low-fitness version of rgba-1 has displaced the high-fitness version.
Do they raise a flag in their article and protest that the theory is all wrong? No, they are almost apologetic, and don’t dare to suggest that there’s anything wrong with the theory. Such stark contradictions between empirical findings and the evolutionary theory of aging have become so commonplace that most everyone has become inured to them. They shrug their shoulders and say, “there must be some hidden benefit associated with the wild-type gene that we have not yet identified.” Part of the reason that they do this again and again is that this is happening in many different labs. Perhaps each researcher in experimental genetics has only discovered one or two anomalies—they may be unaware that their finding is part of a larger pattern.
Fertility in male mice
In August, a very similar discovery was made by a research group (Xiao-dong Wang’s) at the National Institute of Biological Sciences, Beijing, where I have been resident the last two summers. Wang published a groundbreaking study demonstrating programmed reproductive senescence in male mice. The RIPK1-RIPK3-MLKL signaling pathway in wild-type mice was identified as causing a kind of necrosis in male reproductive organs. Inhibiting this pathway caused the males to retain fertility longer.
In their Discussion, they say right off the bat, “The above presented data indicated that the previously unknown physiological function of necroptosis is to promote the aging of male reproductive organs.” But they don’t challenge the pleiotropic theory. Instead—quite typically for experimentalists—they speculate on a possible loophole that will save the theory: Mice sired by older males are less healthy than those sired by younger males. Aha—maybe this is completely unavoidable, and evolution has had to do what it could to prevent these less healthy pups from coming into the world. “We therefore propose that necroptosis in testis is a physiological response to yet-to-be-identified, age-related, TNF family of cytokine(s) that transduces necroptosis signal through the canonical RIPK1-RIPK3-MLKL pathway.” One thing they omit is that cutting off fertility to prevent the births of offspring that are (statistically) less healthy is no more consistent with the orthodox evolutionary theory (based on selfish genes) than are the theories that say aging is an adaptation. Both require group selection, about which orthodox theory is in denial.
An Amish family lacking a death gene
Just this week, Douglas Vaughan’s group at Northwestern University reports identification of a rare genetic “defect” that gives some Amish families longer, healthier lives. The gene called SERPINE1, encoding PAI-1, is mutated and non-functional in these families. The result is longer telomeres, better insulin sensitivity, protection from cardiovascular disease, and longer life expectancy. Conversely, the SERPINE1 must be regarded as an aging gene, having no purpose (we know of) except to hasten the demise of its owner.
What do the authors say about the evolutionary implications of their finding? Exactly nothing.
In Japan, the life-shortening effects of PAI-1 have been known for several years, and there is already a drug in development that blocks its effect. The drug is called TM5441, and a quick Google search located two lab houses [one, two] that sell it for the same exorbitant price.
Gericault – the Raft of Medusa
In Defense of Pleiotropy
To be fair, I should point out that these genes that have no other purpose than to cause early death really are the exception. Almost all genes are pleiotropic in one way or another. Much more common than pure aging genes like SERPINE1 is the situation where genes are dialed up or dialed down late in life in a way that is detrimental (or fatal). The canonical example is mTOR, the target of rapamycin gene. This gene plays an essential role programming the development of a young animal. But when it is turned on late in life, it promotes aging and shortens lifespan.
My position is that this doesn’t let the theory of antagonistic pleiotropy off the hook. Epigenetic programming is every bit as much under the control of evolution as gene sequences. Many genes are turned on and off as needed, and this is a matter of course. A matter of life and death, in fact. If mTOR is turned on late in life, I presume that natural selection has deemed it so.
Pleiotropy is real. Most genes have several functions. But for the pleiotropic theory of aging to be valid, it must be true that tradeoffs are unavoidable. In fact, when the theory was put forth by George Williams , epigenetics had not yet been discovered, and there was yet no notion of turning genes on and off. We now know that this process of gene regulation is an essential part of life in all eukaryotes, and that the timing of gene expression is exquisitely regulated. It makes no sense to imagine (as Williams did) that once you have a gene you’re stuck with it, even if it kills you. In fact, there are many genes that are turned on in youth and turned off in old age, and the effect is almost always to pro-aging. In other words, aging is programmed for the most part not through aging genes like SERPINE1, and certainly not through pleiotropy, but rather through epigenetics. Essential body systems like inflammation and apoptosis are re-purposed later in life as a means of self-destruction.
This opens onto a larger story, the subject of my book.
Mathematical models of aging are my specialty, but I’m not foolish enough to believe in the models. I’m skilled and experienced at modeling so that I can adjust the assumptions to make a model do anything I want it to do. I’ve seen time and again how tiny parameter changes can lead to opposite conclusions.
Mathematical models can prove something is possible. “Nature might arrange things in this way…” But math models can never prove something is impossible. Nature always has the option of arranging things in a way that’s different from the assumptions in your model.
In fact, the paper purports to be a general proof that aging is inevitable in all multicelled life. But there are a few animals and many plants that don’t age. Long periods of negative actuarial senescence (during which the probability of death goes down and down for years at a time) are common in trees, molluscs, and sea animals that keep growing without a characteristic, limiting size. Turritopsis and Silphidae are capable of regressing to larval stage when starved and beginning life anew with a full life expectancy in front of them. Annette Baudisch has made a career studying and documenting “negative senescence”. So the idea that aging is some kind of mathematical certainty has about as much credibility as the authoritative declaration in Scientific American that flight by a heavier-than-air craft was impossible (1904 – more than a year after the Wright Brothers’ first flight).
The paper that appeared last week in PNAS is based on the premise that there is a kind of Darwinian competition among cells in the body. Cells reproduce and mutate within the life of an organism. In their model, somatic evolution–genetic change over time among cells in the same body–must navigate a course between Scylla and Charibdis. The result is that mutations must accumulate, leading either to dysfunctional cells, too weak to do their job, or to cancer cells that have lost their allegience to the body and go on
They call this “aging,” but in fact somatic mutations do not contribute significantly to aging [ref]. Rather, in humans, the causes of aging include runaway inflammation, loss of insulin sensitivity, and thymic involution. (In my view, most of these changes are driven in turn by programmatic epigenetic changes in gene expression.) They redefine the term “senescent cells” to mean “cells that lose vigor due to cellular damage”, and then look for somatic mutations that cause the loss of vigor; but in general usage the term usually applies to cells that have critically short telomeres, or have otherwise entered a senescent state through epigenetic changes.
The bottom line is that Masel and Nelson demonstrate a process that theoretically must kill us in the end, but their proof is silent about how long “in the end” might be, and they offer no evidence that the process they describe has to do with aging as humans (or other animals or plants) experience it. Whatever “in the end” might mean, it must certainly be longer than 80,000 years, because that is the age of the Pando Grove which, last time I checked, qualifies as a multicelled life form.
Scylla and Charibdis
Blowing my stack (forgive me)
No one wants to think that death was handed to us with malice aforethought by evolution/nature/the gods. In African myth, death was an accident caused by the laziness of a canine messenger of the gods. In Judeo-Christian tradition, man would have been immortal if only Adam had not tasted the forbidden fruit. William D Hamilton, one of the most insightful and best-grounded thinkers in evolutionary biology, proved that aging was an inevitable result of natural selection in 1966; forty years on, Baudisch and Vaupel used very similar reasoning to prove the exact opposite–that natural selection could never lead to aging . There are smart, famous people even today who argue that aging derives from the Second Law of Thermodynamics (Hayflick, of all people, is the man who discovered that cell lines run out of telomere).
We want to think that Nature is beneficient, that evolution has done her best by us and made us as strong and durable as possible. If we get old and die, it must be because of something beyond evolution’s control. But it’s just not true. Natural selection first imposed aging on one-celled protozoans, and some of the same mechanisms that cause aging and programmed death in protozoans are active ingredients in human aging today (including telomere shortening and apoptosis). Aging and programmed death have a long evolutionary history, and an ancient genetic basis. We must conclude they exist for a purpose.
William Wordsworth asked, “Who shall regulate with truth the scale of intellectual ranks?”
Winston Churchill told us, “A lie gets halfway around the world before the truth has a chance to get its pants on.”
Arthur C. Clark said, “When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong.”
Young Paul Nelson may be excused for getting carried away by his mathematics, but his mentor (and my former colleague) Joanna Masel ought to know that what they have done is irresponsible. These memes have consequences. Arguably, the small and under-funded community of anti-aging research is the most promising frontier of medical science today, offering a vision that may eclipse multi-billion dollar research programs in cardiovascular disease, cancer and Alzheimer’s disease. Articles like theirs have power because the people who make funding decisions are not experts, they don’t like to be ridiculed, and they’re easily swayed by general sentiment in the research community = people who are already getting the funding.
If we do not correct this impression, it is likely to discredit the most innovative and dynamic field of medical research today.
Disappointing results from Stanford’s first trials of infusions of young blood
Alkahest is a for-profit spin-off from the Stanford lab of Tony Wyss-Coray, doing research with blood plasma from young animals infused into older animals. I first wrote about the project two years ago. The company leapt ahead of animal studies to try infusions of young plasma as a treatment for human Alzheimer’s patients. Last week, Science Magazine reported on a pre-printed meeting abstract: no change in cognitive trajectory of patients who received the infusions.
The people I know best in the field of young plasma are Irina and Mike Conboy. When I visited them last Spring, Irina told me she expected Wyss-Coray’s protocol couldn’t work. The dosage is not sufficient, the duration of treatment is too short, and (according to the Conboys’ research) it is more important to remove pro-aging factors from old blood than it is to add the factors found in young blood.
Wyss-Coray took a chance, and I wouldn’t want to criticize his ambition. But the research world being what it is, this high-profile failure is likely to set back funding for a promising research field. Let’s do what we can to make sure that research by Wyss-Coray, the Conboys and Amy Wagers continues apace.
New Yorker touts the Exercise Pill
An article in last week’s New Yorker began with a long encomium to the drug GW501516, developed by GlaxoSmithkline some 20 years ago, sold in the grey market as Cardarine or Endurobol. Looking behind the headline led me to learn about a family of transcription factors called PPAR. They seem to be promising targets for life extension drugs that are just beginning to be explored.
“In mice, GW501516, either when combined with exercise or at higher doses by itself, induces some hallmarks of [exercise] adaptation such as mitochondrial biogenesis, fatty acid oxidation, an oxidative fiber-type switch and improved insulin sensitivity via AMP-activated protein kinase (AMPK)” [source]
Sounds pretty good, doesn’t it? But
“To its detriment however, tumorigenic effects of GW501516 have been reported and development was discontinued by Glaxo in Phase II clinical trials.”
How serious is the risk of cancer? Are there ways to separate the benefits from the hazards, either by combing with other drugs or by chemical modifications to the structure of GW501516? Is there anyone with a lab who is seeking answers to these questions?
Personally, at age 68 the three main ways that I feel my age are (1) decreased flexibility in yoga postures, (2) decreased speed in running and swimming, and (3) I can’t remember what the third one is. I have charted my steady progression. Swimming and running times are 30-35% longer than when I was 40, and increasing year by year on an accelerating schedule. Exercise is my personal biomarker for age. For reasons of vanity and vitality as well, I eagerly seek pathways to improved performance. I also think that the activities of GW501516 and other PPAR agonists suggest potential for life extension, though there seem to be no lifespan studies either in rodents or humans.
Much of my source for what follows comes from a new paper summarizing exercise-mimetic drug state of the art, and references therein.
PPAR stands for Peroxisome Proliferator-Activated Receptor. Peroxisomes are organelles in every cell that specialize in breaking down fat into short chains that the mitochondria can burn. Thirty years ago, PPARs were discovered in the context of making more peroxisomes, but we now know that their most important function is to increase insulin sensitivity and signal a switch from burning sugar to burning fat.
Stimulating PPAR-α lowers LDL cholesterol and blood triglycerides.
PPAR-γ is a transcription factor that controls creation of new mitochondria. (Mitochondria are the source of cell energy, and as we age, we have fewer of them and they become less efficient, linked to all diseases of age. [from my blog last summer: Part 1, Part 2] Stimulating PPAR-γ improves insulin sensitivity and atherosclerosis. PGC-1α is a protein that turns on PPAR-γ, indirectly creating more mitochondria. Activating PPAR-γ has been discussed as an anti-cancer strategy.
Stimulating PPAR-δ (the modus of GW501516) switches the body from a preference for burning sugar to burning fat. Great for weight loss and also for endurance. You can double the running endurance of mice with GW501516. Presumably, it was rather effective in enhancing performance in human long-distance runners before it was banned in 2009. In calorie-restricted mice and long-lived mutants, PPAR-δ is overactive. (I’ve seen PPAR-β referred to only as similar to PPAR-δ. Maybe they’re the same.)
Joe Cohen at Self-Hacked sings the praises of GW501516. Comments on this blog claim that (1) the increased cancer risk in rats was at very high doses*, and (2) the mechanism in rats doesn’t apply to humans. Other commenters also minimize the cancer risk, but don’t offer references, and they may well be trolls for the companies that profit from GW501516.
“Although peroxisome proliferators have carcinogenic consequences in the liver of rodents, epidemiological studies suggest that similar effects are unlikely to occur in humans.” [source, ref, ref, ref, ref, ref]. “A number of experimental observations suggest that there is a species difference between rodents and humans in the response to PPAR agonists.” [same source] The article goes on to say that PPAR agonists may be more likely to create cancers in rat livers than human livers because rat livers have 10 times the PPAR expression compared to humans. It may be that tumorogenesis comes from the function for which PPARs were named: multiplying the number of peroxisomes. But we now know that PPARs promote new peroxisomes in rodents but not in humans.
Here’s what I’ve been able to find out about PPARs, GW501516 in particular, and cancer:
PPAR is upregulated in colon cancer cells. This shows that cancer causes PPAR, but not that PPAR causes cancer. There are many articles like this one, comprising evidence that activation of PPAR-δ promotes growth of existing tumors of the colon. The evidence is indirect, and gives no suggestion of the magnitude of the risk in humans who have colorectal cancer, let alone whether it in implies a risk for people who don’t have colorectal cancer.
PPAR-δ increases expression of COX2, the opposite of what aspirin and NSAIDs do. NSAIDs decrease risk of cancer, and this suggests both that PPAR-δ increases risk of cancer and that the effect may be offset with NSAIDs.
There are no studies in humans. There are many websites selling Cardarine, from which I guess that at least several thousands of people have taken taken it since 2005. I have seen no sales numbers or estimates of the number of self-experiments, let alone cancer statistics. I have been unable to locate any anecdotes about cancer.
This 2004 review preceded GW501516, and reaches no conclusion. It does, however, state baldly that PPAR-γ (not δ) is generally anti-cancer and that PPAR-α (not δ) causes cancer in rats but not in humans.
I have been unable to find published reports of the origina Smithkline-Glaxo experiment with rats that led to concern about cancer and abandonment of GW501516.
SR9009 is an unrelated mitochondria-growing drug sometimes mentioned in the same articles as GW501516. There are no studies suggesting that it is carcinogenic, but that may be because it is much newer and there are so few studies altogether.
I don’t know whether Cardarine is too dangerous for human use, or whether similar drugs can be developed that target PPR-delta more safely. But I’m outraged that the decision to abandon research on Cardarine has been made by investors in a board room who have no concern for public health and consider only the corporate bottom line. This is an example of the worst kind of collision between capitalism and medicine–a collision which claims millions of casualties each year in the US alone.
I can’t blame the suits in the board room for doing their job, marching to the tune of those who paid the piper. But this is emblematic of a gross failure of our regulation system, the FDA, and the reliance on for-profit drug companies to decide on our nation’s research priorities. We now have (presumably) thousands of people taking a drug which may have large benefits and may have large dangers. Most of them are motivated by wanting to be more buff or more sexy, and they are paying little heed to long-term consequences. And because FDA has washed its hands of responsibility, there is no one even keeping records or collecting data to learn from the massive experiment about long-term health effects of GW501516.
I must admit that RNA splicing factors weren’t on my radar until this week, but I find this new experiment pretty convincing. Eva LaTorre and colleagues from University of Exeter (UK) claim that splicing factors, more than sirtuins, are the pathway by which resveratrol (and analogs) extend life.
Sections of DNA (genes) are transcribed into messenger RNA, which finds its way to ribosomes, where the mRNA is translated into protein molecules. But there is an in between step (in eukaryotes, but not in bacteria). The DNA contains not whole (contiguous) genes but pieces of genes that need to be spliced together to assemble instructions for a whole protein. Large sections of the DNA, called introns, are not intended for coding, and they need to be spliced out. And, in fact, the pieces can generally be spliced together in different ways to make different useful proteins. The work of splicing is performed by molecular complexes called splicing factors. This is a process to which I had not given much thought until reading this article, but apparently it is a crucial step in epigenetics. Epigenetics, the process of turning genes on and off, seems to get more complex with each passing year.
Resveratrol was identified about 15 years ago as a compound that extends lifespan in many species (but perhaps not in mammals). Resveratrol has many effects, but the primary mode of action has been thought to be through SIR2 (or SIRT1) or related compounds called sirtuins that are selective gene silencers. But the LaTorre group set out to show that the anti-aging benefit was through splicing factors rather than sirtuins. They synthesized variations on the resveratrol molecule and tested them until they found one that promotes slicing factors but has no effect on sirtuins.
Using this resveratrol analog, they were able to turn senescent cells back into fully functioning cells, with restored telomeres and other epigenetic changes. They demonstrated that this was accomplished through splicing factors, and without sirtuins.
All this was done in (human) cell cultures, and it the horizons are now open to see what effect such rejuvenation has at the whole body level.
* Of course, there is no established dosage for GW501516, but pills come in 10mg and 20mg typically, corresponding to ~0.1 to 0.3 mg/Kg. The highest doses I’ve seen discussed in humans are ~2mg/Kg daily, nominally the same as the rat dosage.
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