Biological Clocks: Why We Need Them, Why We Cannot Trust Them, How They Might Be Improved.

Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)). In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading. Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body's primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.

How does the body know how old it is?

Based on the ideas of R. A. Fisher, neoDarwinism came to dominate evolutionary science in the first half of the wentieth entury, and within that perspective aging could never be an evolved adaptation. But as the genetic and epigenetic mechanisms of aging came to be elucidated in many species, the signature of an adaptation became clear. Simultaneously, evolutionary theorists were proposing diverse selective mechanisms that might account for adaptations that are beneficial to the community, even as they imposed a fitness cost on the individual. Epigenetic conceptions of aging gained currency with the development of methylation clocks beginning in 2013. The idea that aging is an epigenetic program has propitious implications for the feasibility of medical rejuvenation. It should be easier to intervene in the body's age-related signaling, or even to reprogram the body's epigenetics, compared to brute-force repair of all the physical and chemical damage that accrues with age. The upstream clock mechanism(s) that control the timing of growth, development, and aging remain obscure. I propose that because of the need of all biological systems to be homeostatic, we should expect that aging is controlled by multiple, independent timekeepers. A single point of intervention may be available in the signaling that these clocks use to coordinate information about the age of the body. This may be a way of understanding the successes to date of plasma-based rejuvenation.

A laboratory and simulation platform to integrate individual life history traits and population dynamics.

Understanding populations is important because they are a fundamental level of biological organization. Individual traits such as aging and lifespan interact in complex ways to determine birth and death and thereby influence population dynamics. However, we lack a deep understanding of the relationships between individual traits and population dynamics. To address this challenge, we established a laboratory population using the model organism C. elegans and an individual-based computational simulation informed by measurements of real worms. The simulation realistically models individual worms and the behavior of the laboratory population. To elucidate the role of aging in population dynamics, we analyzed old age as a cause of death and showed, using computer simulations, that it was influenced by maximum lifespan, rate of adult culling, and progeny number/food stability. Notably, populations displayed a tipping point for aging as the primary cause of adult death. Our work establishes a conceptual framework that could be used for better understanding why certain animals die of old age in the wild.

A Clinical Trial Using Methylation Age to Evaluate Current Antiaging Practices.

Recent advances in the technology of "aging clocks" based on DNA methylation suggest that it may be possible to measure changes in the rate of human aging over periods as short as a year or two. To the extent that methylation (and other biomarkers) are valid surrogates for biological age, the testing of antiaging interventions has thus become radically cheaper, faster, and more practical. Together with colleagues at UCLA, I have initiated a clinical trial to evaluate some of the most popular antiaging strategies currently deployed by "early adopters" in the lay community of personal health activists. We are recruiting 5000 subjects, age 45-65, and interviewing them in detail about their diet, drugs and supplements, exercise, social, and other practices that plausibly contribute to modulate the rate of aging. They agree to submit blood samples for analysis of methylation age at the beginning, middle, and end of a 2-year test period. Primary endpoint is the difference in methylation age over the course of 2 years. We are in the process of developing a specialized clock, optimized for individual differences over time. Results will be viewed as an exploratory study to identify synergistic combinations of age-retarding treatments. It is our expectation that there is a great deal of redundancy in the strategies that have been researched and promoted to the aware public; thus, most combinations can retard the rate of aging by only a few percent, consistent with the best known single measures. However, we hope that among the many strategies that our subjects have adopted, there will be some combinations that synergize and achieve age retardation by ≥25% or more. A mock-up analysis of computer-generated data has been performed to fix parameters of the study, and confirm that such combinations will be able to be detected with good probability, should they exist. All data (redacted for privacy) will be open sourced, available to the scientific community and to the public.

Combining Life Extension Treatments: A Proposal for High-Throughput Testing in Rodents.

An experimental design is proposed for high-throughput testing of combined interventions that might increase life expectancy in rodents. There is a growing backlog of promising treatments that have never been tested in mammals, and known treatments have not been tested in combination. The dose-response curve is often nonlinear, as are the interactions among different therapies. Herein are proposed two experimental designs optimized for detecting high-value combinations. In Part I, numerical simulation is used to explore a protocol for testing different dosages of a single intervention. With reasonable and general biological assumptions about the dose-response curve, information is maximized when each animal receives a different dosage. In Part II, numerical simulation is used to explore a protocol for testing interactions among many combinations of treatments, once their individual dosages have been established. Combinations of three are identified as a sweet spot for statistics. To conserve resources, the protocol is designed to identify those outliers that lead to life extension greater than 50%, but not to offer detailed survival curves for any treatments. Every combination of three treatments from a universe of 15 total treatments is represented, with just three mice replicating each combination. Stepwise regression is used to infer information about the effects of individual treatments and all their pairwise interactions. Results are not quite as robust as for the dosage protocol in Part I, but if there is a combination that extends lifespan by more than 50%, it will be detected with 80% certainty. These two screening protocols offer the possibility of expediting the identification of treatment combinations that are most likely to have the largest effect, while controlling costs overall.

An epigenetic clock controls aging.

We are accustomed to treating aging as a set of things that go wrong with the body. But for more than twenty years, there has been accumulating evidence that much of the process takes place under genetic control. We have seen that signaling chemistry can make dramatic differences in life span, and that single molecules can significantly affect longevity. We are frequently confronted with puzzling choices the body makes which benefit neither present health nor fertility nor long-term survival. If we permit ourselves a shift of reference frame and regard aging as a programmed biological function like growth and development, then these observations fall into place and make sense. This perspective suggests that aging proceeds under control of a master clock, or several redundant clocks. If this is so, we may learn to reset the clocks with biochemical interventions and make an old body behave like a young body, including repair of many of the modes of damage that we are accustomed to regard as independent symptoms of the senescent phenotype, and for which we have assumed that the body has no remedy.

Is programmed aging a cause for optimism?

Aging is now viewed as programmed under genetic control by a growing minority of evolutionary biologists, and a larger proportion of researchers in gerontology. The hypothesis of programmed aging has been regarded as encouraging for anti-aging science. Some mechanisms of programmed aging may present ready targets for medical interference [mitigation alleviation attenuation], while other kinds of programmed mechanism may yet prove to be refractory. The most promising possibility is that the machinery responsible for maintenance of the vibrant and youthful state of the body is never really lost, but de-commissioned by hormonal signals in the aging body; restoring a youthful signaling environment should then be sufficient to prompt the body to restore itself. But it is also possible that aging may be programmed in a way that does not facilitate anti-aging interventions. We identify two possible cases: In the first, the body is programmed to age via neglect rather than by affirmative self-destruction, so that damage is accumulating that the body is beyond the body's power to repair. In the second, aging is controlled by an epigenetic clock whose workings are so intricate as to be intractable for human mastery in the foreseeable future. There is substantial evidence that first of these is not a likely scenario, but the jury is still out on the second.

Aging is not a process of wear and tear.

The idea that bodies wear out with age is so ancient, so pervasive, and so deeply rooted that it affects our thought in unconscious ways. Undeniably, many aspects of aging, e.g., oxidative damage, somatic mutations, and protein cross-linkage are characterized by increased entropy in biomolecules. However, it has been a scientific consensus for more than a century that there is no physical necessity for such damage. Living systems are defined by their capacity to gather order from their environment, concentrate it, and shed entropy with their waste. Organisms in their growth phase become stronger and more robust; no physical law prohibits this progress from continuing indefinitely. Indeed, some animals and many plants are known to grow indefinitely larger and more fertile through their lives. The same conclusion is underscored by experimental findings that various insults and challenges that directly damage the body or increase the rate of wear and tear have the paradoxical effect of extending life span. Hyperactive mice live longer than controls, and worms with their antioxidant systems impaired live longer than wild type. A fundamental understanding of aging must proceed not from physics but from an evolutionary perspective: The body is being permitted to decay because systems of repair and regeneration that are perfectly adequate to build and rebuild a body of ever-increasing resilience are being held back. Regardless of the reason for this retreat, it should be more fruitful to focus on signaling to effect the ongoing activity of systems of repair and regeneration than to attempt repair of the manifold damage left in the wake of their failure.

Senescence as an adaptation to limit the spread of disease.

Aging has the hallmarks of an evolved adaptation. It is controlled by genes that have been conserved over vast evolutionary distances, and most organisms are able to forestall aging in the most challenging of environments. But fundamental theoretical considerations imply that there can be no direct selection for aging. Senescence reduces individual fitness, and any group benefits are weak and widely dispersed over non-relatives. We offer a resolution to this paradox, suggesting a general mechanism by which senescence might have evolved as an adaptation. The proposed benefit is that senescence protects against infectious epidemics by controlling population density and increasing diversity of the host population. This mechanism is, in fact, already well-accepted in another context: it is the Red Queen Hypothesis for the evolution of sex. We illustrate the hypothesis using a spatially explicit agent-based model in which disease transmission is sensitive to population density as well as homogeneity. We find that individual senescence provides crucial population-level advantages, helping to control both these risk factors. Strong population-level advantages to individual senescence can overcome the within-population disadvantage of senescence. We conclude that frequent local extinctions provide a mechanism by which senescence may be selected as a population-level adaptation in its own right, without assuming pleiotropic benefits to the individual.

How evolutionary thinking affects people's ideas about aging interventions.

Evolutionary theory has guided the development of antiaging interventions in some conscious and some unconscious ways. It is a standard assumption that the body's health has been optimized by natural selection, and that the most benign and promising medical strategies should support the body's efforts to maintain itself. The very concept of natural healing is a reflection of evolutionary thinking about health. Meanwhile, a developing body of experimental evidence points to the startling hypothesis that aging is a metabolic program, under genetic control we are programmed for death. Evolution has provided that the aging program can be abated in times of stress, e.g., caloric restriction. CR mimetics are already recognized as a promising avenue for antiaging research. Beyond this, there are two ancient mechanisms of programmed death in protists that have survived half a billion years of evolution, and still figure in the aging of vertebrates today. These are apoptosis and replicative senescence via telomere truncation. Most researchers have been wary of modifying these mechanisms because they are known to play a stopgap role in cancer prevention. But intriguing evidence suggests that, despite some counter-carcinogenic function, the net result of both these mechanisms may be to shorten lifespan. Thus, interventions that suppress apoptosis and that preserve telomeres may be promising avenues for life extension research. A third element of the body's self-destruction program co-opts the inflammation response. Epidemiological evidence suggests that NSAIDs including aspirin protect against atherosclerosis, arthritis, and some forms of cancer. It may be that aging engages an autoimmune response that can be modified by drugs acting more narrowly on this same pathway. The existence of an evolutionary program that controls aging from the top down supports a new optimism concerning the types of antiaging interventions that are possible, and the likelihood that simple strategies may have dramatic results without dramatic side-effects.