THE 55: A First Introduction

Rob Paterson & Michael R. Rose

Welcome to Michael Rose’s 55, an overarching context that will enable you to use nature’s rules to make sense of your health and take action to make your life much better.

You will do this by changing how you live. Not as a result of yet another fad but as the result of knowing the scientific context. You will be the agency of your own health.

Up until now, for most of us, medicine has been the controlling authority of health. And that medicine has been reductionist and simplistic. For that is how physicians have been trained to see the human body. The connections between the parts got lost in the desire to find simple-minded answers in the parts. Connections between people and their environment were obscured because of the medical-industrial focus on parts, and their mechanical explanation, modification, and treatment.

In this machine-world of crude control, the vast and subtle networks that underpin biology have been ignored and trampled. Everything was made simple for only the simple could be controlled. Everything had to be explained by simple conveyor-belt pathways, and treated accordingly. To be healthy, we were told, we had to become compliant patients, we had to give up on our true human nature.

To do well in the medical-industrial world, we had to take drugs and suffer mutilating surgeries, even for the most trivial problems. If you are diabetic, take insulin. Wrinkles and sags, get cosmetic surgery. Uncontrollable appetite, bariatric surgery. A diagnosis of heart disease is treated first with drugs, then bypass surgery, and finally a transplant.

But the new biology of our time, born circa the year 2000, is showing that this brutal style of medicine is not just inefficient. It is in fact directly contrary to the subtle networks that sustain life itself. It violates our evolutionary history, and it rapes the health that evolution gave us.

Just as Einstein and the modern physicists banished simple-minded physics, 21st Century biology is demolishing the crudely mechanistic thought of molecular biology. In its place we now see glittering webs of life. And these webs are not just mystical objects fit only for worship. Rather they are the very stuff from which the new sciences of life are being spun.

Using the 55, we will show you how you can use the new biology to take a better approach to your health, to your body, and to the way you live in the world. From this new way, you will find the comfort and the understanding that you used to give up when you entered the clinics and the hospitals that have been the temples of the reductionist thuggery of the 20th Century medical-industrial complex.

55 Theses on the Power and Efficacy

Of Natural Selection for Sustaining Health

Dr. Michael R. Rose,

Professor of Ecology and Evolutionary Biology,

University of California, Irvine, CA 92697-2525

Out of respect for both science and medicine, the following propositions are open for discussion throughout the World-Wide Web.

Preface

These theses are intended to supply a re-visioning of the scientific foundations of health and medicine. Rather than making small adjustments to a body of medical knowledge which has been developing by accretion since the time of Hippocrates, this re-visioning starts with a firm rejection of the present reductionist foundations of medicine. The human body is not an inert vessel that can be fairly viewed in terms of a definable set of chemical reactions. Rather, it is a product of an evolutionary process that has been ongoing for billions of years, an evolutionary process that has been directed by natural selection. As such, it will be argued that evolutionary biology provides the only secure foundation for understanding our health and for improving the practice of medicine.

There are two misunderstandings that this basic statement might engender, misunderstandings which must be immediately flagged as errors. I will now dispose of these errors, before getting on with the main business at hand.

The first misunderstanding would be the notion that the present perspective marks a break from scientific materialism, that somehow it is being proposed that there is something basically wrong with physics, chemistry, or even organic chemistry. Such an interpretation would be quite wrong. All of physics and chemistry are fully accepted on the present view. Instead, what is rejected is the conjecture that physics and chemistry supply enough in the way of scientific theory or experiment for understanding the foundations of health and medicine which, as argued here, are evolutionary. But evolutionary theory is built on top of the physical sciences, and does not tilt against them.

The second misunderstanding would be that the present effort is an attempt to merely add evolutionary ideas to conventional reductionist biology and medicine. Some scientists have made such attempts, and those attempts are not entirely without merit. But the present view is that the scientific foundations which are offered for medicine in the medical schools of the United States and other Western countries, with their characteristic molecular-biological reductionism, are not valid scientifically. This is not to say that such foundations were not a reasonable basis for medicine in the period from 1950 to 1975. They were. But the last 35 years of research in biology have destroyed the scientific models that held sway during those 25 years, and part of the present treatment will be to present the gist of that recent research.

THE 55: Further Introductory Notes

If you are a person who is instinctively inclined to skepticism, and is not an evolutionary biologist, let me give you an alternative way of approaching the 55 Theses.

Repeatedly in the history of our species, we have come up against key technological limits. The first proto-humans developed the core adaptation of technology some four or five million years ago. That is, they were the first species to adopt the use of hand-held tools, extensive food preparation, and the like to escape the basic animal niche based on built-in weapons and raw foods. Ever since, our evolutionary history and our biological fitness have been determined by our use of technology.

For the first few million years of our evolution, we were chiefly gatherers and scavengers, subsisting on a varied diet. We obtained access to food by using digging and cutting implements, and we fostered our digestion of that food by cleaning, pounding, cooking, and otherwise preparing it. During that time we evolved an increased capacity to digest starches, probably from the consumption of underground storage organs, like cooked tubers. We evolved adaptations for walking efficiently and handling our tools effectively.

Next our immediate ancestors spent one or two million years evolving adaptations for hunting, which was added to our already diverse repertoire of behavioral adaptations for finding food. During this period, we became markedly more intelligent than all other animals for the first time, in part because we could get the nutrients to build and sustain large brains. During this period our bodies adapted to high levels of meat and animal fat consumption.

Quite recently, evolutionarily speaking, some human populations adopted the systematic cultivation of grass species, like wheat, and the husbandry of other mammals for their milk. Such populations were then strongly selected for physiological adaptations to an evolutionarily novel diet.

This is a complicated evolutionary history, with three significant changes of direction. Taking this complex evolutionary history into account requires a deep understanding of how natural selection does, and does not, produce effective biological adaptations. Such adaptations, and their limitations, determine human health.

Unfortunately, these evolutionary foundations for human health have been generally neglected by most biologists. The medical establishment has been dominated by the reductionist cell-molecular wing of biology, which has had limited interest in evolutionary research, and even less understanding of its results. Thus extremely crude views of the evolutionary foundations of human health have prevailed in medical schools, and in the practice of medicine. On the other hand, the very few evolutionary biologists who work in the universities of our time have paid little attention to the foundations of medicine. There are too few of us, we generally feel, so we focus on sustaining the flickering fires of our field against the prevailing intellectual darkness of present-day biology.

The consequences of this failure to engage with the evolutionary foundations of human health are all around us. Modern-day medicine is effective when it is confronting threats that are not complicated evolutionarily, such as mechanical injuries and some acute infections. But it has singularly failed to address the majority of ailments that now impinge on the world’s population, from the new epidemic of type 2 diabetes to rampant cardiovascular disease and cancer. Against the chronic diseases of our time, medicine has tried remedies from the palliative to the heroic. But cure and prevention have been generally wanting.

The result is an economic and political calamity. Few of the industrialized economies have a fiscal solution for the tidal wave of aging and impaired adults that is hitting them. When a large fraction of adults cannot work because of chronic disease, their retirement from the work-force and the expense of their ineffective medical treatment are not affordable.

The only way to escape this aging tsunami is to bring about a radical solution to the medical problems of aging, where the insight that this is the key systemic problem facing most countries is spreading rapidly at this moment. The problem facing us now is how to achieve this solution.

Molecular and cell biologists propose that we increase the resources devoted to their ad hoc scrambling after a solution to the aging problem. After decades of failure to make much scientific progress, they want even more resources to continue down their path of futility, where aging is concerned.

At the same time as the reductionist biological orthodoxy has singularly failed to scientifically solve the problem of aging, evolutionary biology has made rapid, radical, and sustained progress with the same scientific puzzle. Preventing us from bringing evolutionary biology’s scientific resources to bear on the practical problems of human aging, as the reductionist biomedical establishment has done, will ensure economic and political catastrophe.

In the 55 Theses themselves, I outline an alternative view of health based on evolutionary research. In the ancillary explanatory material that accompanies these theses, I attempt to provide means of unpacking and understanding the 55 for those who are not evolutionary biologists. Once the 55 have been discussed widely and openly, we can see if the current vested interests can be circumvented in order to rescue our health and our political economies.

THE 55: The Scientific Challenge

Biology is in a state of transformation. Much like the re-foundings of biology that took place after 1800, 1859, 1900 and 1952, the first decade of the 21st Century has seen a major upheaval in biology. The four previous revolutionary episodes in biology arose from the founding moments of non-creationist scientific biology, evolutionary biology, genetics, and molecular biology, respectively. The present revolutionary episode comes from the birth of genomics, the cutting edge of 21st Century biology.

The genomic revolution has shown us that genome sequences, gene regulation, and gene function are vastly more complex than previously thought. The conceit that we could unravel, dissect, and explain most biological functions in terms of simple molecular-genetic pathways is defunct. What we are facing instead is complex networks of many genes, still more transcripts, and exponentially more molecular interactions underlying each significant feature of development, function, and pathophysiology.

Traditional models for pharmaceutical development and clinical medication are now in tatters. Yet the power of the new genomic tools gives us unheralded opportunities to systematically identify the molecular and cellular foundations of infections, genetic disorders, and chronic idiopathic disorders. What to do?

It is obvious to most biologists that solving non-trivial scientific problems in biology will depend on the use of bioinformatic tools to process vast arrays of genomic, transcriptomic, metabolomic, and still other omic data. The characteristic feature of such data is its sheer magnitude. But still worse is the fact that the crude syllogistic tools of traditional biological reductionism are wholly inadequate to make sense of such data.

The time has arrived for biology to re-found itself, just as it has four times already, about once each half-century. In this re-founding, the principles of complexity and quantitative analysis have to be accepted. As in the re-founding of physics at the start of the 20th Century, after Einstein’s 1905 publications, we have to give up the traditional intuitive concepts of biology, just as physics gave up the simple certitudes of Newtonian physics.

But if complexity and quantitative analysis have to be fully accepted by the biology of our time, how can we master these challenges? That is, what are the fundamental tools that we can turn to in order to make sense of the new biology?

I think that the answer is clear. Biology has to be re-founded using mathematically formal theory derived from evolutionary, genetic, and molecular first principles. Fortunately, evolutionary geneticists have been developing such tools since the 19teens, about a century ago. The application of those tools was limited, prior to 2000, by a lack of genomic data. But now that such data are at hand, indeed gushing forth, we are entering a golden age for the application of evolutionary genetic tools to the problems of biology.

This does not mean that all the work has already been done. Twentieth-century evolutionary geneticists were working in a vacuum due to a lack of critical data. As such, like sighted people emerging from a period of prolonged darkness into daylight, they now have adjusting to do. But they have the formal theoretical methods and experimental tools to solve the key problems that challenge biology in our time.

One of the first applications of the new evolutionary genetics has been a transformation of our understanding of aging. This has been my particular focus as a scientist. It is this problem, in particular, where the application of evolutionary genetics to the challenges of the new biology is particularly straightforward. This arises for two reasons. First, aging is a problem that has utterly defeated all non-evolutionary biological research strategies. Second, aging is a problem that is readily addressed by applying evolutionary genetics in the context of the new genomic biology.

In the 55 theses, I outline a 21st Century approach to the problems of aging, both as a general scientific puzzle and as a major medical challenge in our time. The 55 are thus, in my opinion, a paradigm for the new biology being born around us.

I should be clear that I do not see the 55 specific conclusions that I adduce as final. Instead, I see them as starting points for a very different approach to the scientific problems posed by aging in general, and human aging in particular. But once the 55 are adopted as starting points, it is fairly straightforward to implement research strategies for addressing the many important questions that these starting points raise.

On the technological side, I see little promise in continuing to develop pharmaceuticals and other medical treatments for age-associated disorders based on erroneous science. Yes, sometimes useful drugs and medical procedure are found adventitiously. Likewise, bridges and cathedrals were built long before modern physics got going. But once good scientific tools were made available to engineers, architects, and chemists, their ability to build better roads, buildings, and machines exploded. That, after all, is how industrial civilization was built. Likewise, I look forward to a new medicine that is founded on the radically more powerful biology which is now at hand.

The biological fitness of a population is the average net reproduction of its members, which in turn is determined by their capacity to survive and reproduce; biological fitness is at the core of health.

The starting point of the present theses is to take Darwinian fitness as the key foundation for understanding health. Stripped of such a Darwinian foundation, a wide spectrum of alternative definitions of health can be offered as the central focus for medicine: biochemical efficiency, athletic performance, freedom from disease, and so on. None of these definitions have particularly well-formulated scientific foundations, and certainly none of them connect to a scientific theory with the power, range, and depth of evolutionary theory. It would be interesting to provide an historically well-developed presentation of the many alternative conceptions of health that have been promulgated and debated over the last few thousand years of Western medicine, leaving aside the more exotic traditions of traditional Eastern medicine or the shamanistic practices of pre-agricultural societies. But instead, I will just get on with the task of developing of a coherent, scientifically formulated, alternative to the various confusions that are widely on offer.

Darwinian fitness is a single numerical measure which combines all the individual probabilities of survival and reproduction of a population of individuals in the particular environment in which it finds itself. The mathematical form of this measure takes different forms with different population demographies, but it can always be defined in a scientifically cogent manner.

So why is Darwinian fitness a useful place to start developing the scientific foundations of medicine? In all the biological sciences, there are few other variables for which we have such well-developed theory. Moreover, it is Darwinian fitness that is the key to the arc of evolution. This Darwinian variety of fitness is the key determinant of natural selection, and natural selection is the steering wheel for evolution.

But natural selection is not an all-powerful determinant of evolutionary processes. Instead, it is constrained, limited, and often thwarted by other evolutionary factors. Such constraints are the main theme of the first ten theses. It is not possible to think about natural selection intelligently unless the constraints on its action are kept firmly in mind. In particular, it is not a synonym for a benign, all-powerful, cosmic force that always maximizes our Darwinian fitness.

2. Natural selection reliably produces high levels of biological fitness, and thus good health, only under the environmental conditions in which it has been acting for many generations.

A common caricature of evolution by natural selection is that it produces some type of universal progress that is sustained and predictable over millions of years. Not only is this NOT how present-day evolutionary biologists think of evolution, it isn’t even how Charles Darwin himself thought of the effects of evolution by natural selection. This is, unfortunately, how many naïve and perhaps temperamentally optimistic intellectuals have thought of evolution by natural selection. Perhaps evolutionary biologists have little right to complain about this; the perversions and misappropriations of Einstein’s relativistic mechanics in twentieth-century popular and intellectual culture were even more ludicrous. But this misinterpretation of evolution by natural selection has certainly impeded the use of this central biological theory by medicine, because it strips evolutionary biology of much of its salience as a foundation for medicine.

The key point is that natural selection predictably acts to increase fitness only in the environments in which it has long acted. This is why, for example, colonizing other parts of our solar system is such an inherently difficult proposition. Few, or no, species on this planet have adaptations that would enable them to thrive in the environments supplied elsewhere in our solar system. At a less extreme level, most insects have extreme difficulty surviving and reproducing during circumpolar winters, as do most plants. Environmental conditions define the context for natural selection. And such environments are defined not only by physical conditions; they also involve the biological communities of species found in particular habitats, whether those species are competitors, prey, predators, or pathogens.

This constraint on natural selection is not only a matter of habitat. It is also a matter of time. Natural selection takes many generations to produce high levels of fitness in a particular environment. Since particular environments require the evolution of corresponding particular biological functions, generally called “adaptations,” in order to achieve high levels of fitness, the longstanding environmental history of any population determines which specific adaptations that population will possess.

3. Health and adaptation thus reflect the action of natural selection on a population in its previous environments, not its present environment, when these differ.

For the purpose of re-founding medicine scientifically, theses 2 and 3 direct us to pay particular attention to the sequences of environments that humans have been exposed to during our evolutionary history. It is fanciful to suppose that, because our species has been in existence for several hundred thousand years of evolution, it is fully adapted to any environmental conditions that it might encounter.

And this point is still more profoundly important when we consider the extent to which our environments have been transformed over the last century of rapid technological change. Just four or five human generations are far too few to have given us adequate adaptations to our present environment. Instead, what adaptations we have, and thus the conditions under which our fitness is likely to have been maximized, reflect the impact of natural selection on our evolution prior to the advent of our present, highly technological, industrial environment.

Thus evolution by natural selection has supplied us with adaptations only to environments in which we have lived for many centuries. But this does not then immediately imply any simple or obvious set of inferences about how medicine can best manage human health or treat our diseases. For the action of natural selection is subject to still other limitations, well beyond the vagaries of environmental history.

It is these further limitations on the action of natural selection that we turn to next.

4. Natural selection results in the evolution of good health only when there is sufficient heritable variation affecting survival and reproduction.

Natural selection accomplishes nothing without an adequate and appropriate supply of genetic variation on which to act. That is why dolphins and whales breathe air in order to get oxygen to their cells; they haven’t had genetic variants that natural selection could have acted on in order to re-evolve gills.

What this means for medicine is that there are a lot of good things that natural selection might have accomplished in our evolution, but didn’t. The most concrete, and indeed deadly, example of this is that humans haven’t evolved the capacity to give birth through their abdominal walls. As a result, for most of the last million years, one of the most dangerous things that happened to each human was being born. That’s because our birth requires that our evolutionarily enlarged neonatal cranium has to pass through the narrow bottom opening of the pelvis. It would have been brilliant if natural selection had solved this “design problem,” but again, like the lack of gills in whales, it didn’t have any genetic variation that it could have used to solve this design problem.

In some cases, this failure of natural selection is remarkably specific at the genetic level, yet medically devastating. The hemoglobin gene that produces sickle-cell anemia when the normal gene is absent kills thousands of people every year. But in this case natural selection actively sustains this allele in sub-Saharan African populations because genomes that have one copy of the sickle-cell gene together with a copy of the normal gene are better able to resist malaria. In an ideal world, there would be a hemoglobin gene that confers resistance to malaria without causing a deadly genetic disease. But mutation has yet to produce such a variant in sufficient numbers for natural selection to make use of it in regions where malaria is common.

Thus there is an entire spectrum of medical problems which arises from this key limitation on what natural selection can accomplish. When we can conceive of a simple morphological or biochemical solution to a medical problem, it is not a falsification of the evolutionary foundations of human health that natural selection did not produce it. Natural selection is severely limited in what it can accomplish, not least because of this problem of missing ideal genes.

5. Natural selection produces good health only when population size is large enough to overcome genetic drift; inbreeding reliably impairs health in outbreeding species.

Many members of the human species have a great propensity to mate with other humans. You may know such a person yourself. This makes eminent evolutionary sense: we can’t reproduce asexually or by self-fertilization. It is this absolute requirement that we had to have sex to that generated our high levels of genetic variability. We are one of nature’s outbreeding species, a species in which mating is not normally kept within close families, unlike some social insects and fig wasps, or even the naked mole rats of Africa.

This feature of our mating history gives rise to a medical problem which should be more widely appreciated: mating within small ethnic groups gives rise to an increased frequency of genetic diseases caused by recessive deleterious genes. One of the most horrifying examples of this problem is the prevalence of Tay-Sachs disease in the offspring of matings among Ashkenazi Jews. Tay-Sachs is an incurable and fatal disease that causes severe brain degeneration in young children, with accompanying blindness, mental disability, and severe pain. This medical tragedy arises insidiously from the common human inclination to mate with someone from a similar background.

Generally, mating among biological relatives is associated with a wide variety of impairments, from shorter stature to lower IQ. This is an effect that natural selection abhors; as a result the best single example of an apparently inherent human behavioral pattern is an aversion to mating with siblings or parents.

This is the first thesis which leads to a simple piece of medical advice. People should either avoid having children with individuals with whom they share ancestry or, if they decide to go ahead with such a plan, they should actively seek genetic counseling and the best prenatal genetic diagnostics available. Fortunately, we are entering an era of rapid progress in genetic characterization, and we can all hope that ways will be found to circumvent the tragedies that genetic diseases produce.

6. Natural selection produces good health only when new deleterious mutations are rare or small in magnitude; very few novel mutations will have large and generally beneficial effects, in an environment to which a population is well-adapted.

Mutation is the source of the genetic variation that natural selection acts on. But very few new mutations are beneficial. Instead, the vast majority of mutations have no selectable benefit, or are actually deleterious. It is only in comic books or bad science fiction that mutations suddenly produce a much-improved human.

This has significant implications for human health. Circumstances that elevate mutation rates will generally impair health. The best example of a situation where this arises is exposure to radiation. At extreme levels, radiation directly degrades biological tissues, causing immediate death in the worst cases.

But more subtly, radiation also readily increases mutations rates in exposed tissues. In somatic tissues, such mutation can lead to combinations of mutations which allow unlimited cell proliferation. When somatic selection among such mutant cells operates over time, selection within the body can favor the most proliferative of these mutant somatic cells, leading to the development of malignant cancer.

In the cells that will eventually produce sperm or eggs, mutation will lead to mutant genes that can be transmitted from generation to generation, potentially causing a trail of havoc in the descendants of the individuals whose testes or ovaries were irradiated.

The obvious medical significance of these basic points it that we should avoid exposure to radiation. There are five contexts in which we are routinely exposed to elevated levels of radiation: (i) sun exposure; (ii) diagnostic medical or dental radiology, (iii) high-elevation flight, (iv) radon emissions from basements, and (v) proximity to radioactive wastes, such as those produced by nuclear power plants, mining, and medical radiology. This is a spectrum of exposure risks from the unavoidable to the relatively rare and avoidable.

In addition to radiation, there are a number of synthetic and naturally-occurring substances that cause mutations as a result of chemistry alone. Most of the worst of these are products of scientific or industrial chemical synthesis. On the other hand, Bruce Ames and others have found weaker carcinogens in many of the food products that we routinely ingest, from caffeine to burnt meat.

7. Natural selection will sustain nucleotide sequences that foster biological fitness however numerous and however indirect their benefits, making the genetic foundations for the evolution of health genome-wide and complex.

The kinds of experiments that most biologists favor involve studying large-effect mutations and other ways of mutilating or disrupting experimental animals. It is an irony of much molecular genetic research that it often studies the physiology of large-effect mutations produced by radiation and other means. Experimental animals with such mutations are unlikely to be a useful guide to the physiological variation that arises from the kind of high-fitness genes that are more likely to be common in large human populations. Yet molecular biologists are fond of reasoning from (a) the large experimental signals that such mutants produce to (b) the functional underpinnings of normal physiological function.

Sometimes this works. If a biologist carefully destroys the reproductive organs of a group of animals using irradiation or genetic engineering, but does not inflict severe adverse side-effects, these animals will usually live longer compared to intact controls. This reveals a cost of reproduction that is one of the more durable, if not quite universal, findings of research on aging. An interesting exception is women, who do not appear to live longer if they undergo hysterectomy and ovariectomy. But men, at least in American institutions that used to castrate incarcerated “mental defectives,” who are castrated do live longer.

On the other hand, producing inbred laboratory stocks and then mutating them has been shown to give misleading results in a significant number of cases. This doesn’t mean that such experiments can never be used to reveal how animals work. But it does mean that such experiments can’t be generally trusted.

As an alternative approach, evolutionary biologists, quantitative geneticists, and other types of more Darwinian biologists prefer to work with naturally occurring genetic and environmental variation. This reflects the common assumption among such biologists that natural selection will often favor genetic variants and physiological responses to environmental variation that are limited in their effects, rather than large in their effects. Furthermore, this kind of biologist generally supposes that genetic variation at many sites throughout the genome will underlie the evolution of functional characters, like those which sustain both Darwinian fitness and medical health.

One way of looking at this difference between these two types of biologists is that the first type, let us call them molecular biologists or reductionists, like to suppose that organisms are assembled from well-defined, machine-like, large-effect pathways. The second type of biologist allows that a few cases like that may evolve, but that much of the underpinnings of normal function is genetically and physiological complex. Let us call these Darwinian or evolutionary biologists, as this is fairly close to Darwin’s own thinking on this topic. Darwin and subsequent generations of evolutionary biologists have emphasized that natural selection can act on many inherited variations, even relatively subtle heritable genetic differences. Thus a Darwinian view of health is naturally inclined to emphasize the idea of many contributing genetic and biochemical factors underlying healthy function, not a small number.

8. This complex genomic foundation for adaptation in turn produces a still more complex network of interacting molecules that sustain survival, health, fertility, and function.

Arising from the genetic complexity of healthy function is a still more complex set of interacting products of DNA sequences: all the RNAs transcribed from DNA and all the proteins that are made from RNAs. These in turn interact with each other, with other molecules that make up cells, and even with the DNA from whence they came.

So the genomic complexity of the DNA that underlies health is just the simplest dimension of healthy function. What is erected from the linear strands of DNA that make up our genomes is three-dimensional, and teeming with a fury of interactions. Many of these interactions happen quickly, while others proceed only slowly. But this network is all in motion and in interaction.

It has been the long-standing, indeed hubristic, conceit of molecular and reductionist biology that this vast three-dimensional matrix of furiously interacting gene-products can be understood using such simple linear paradigms as their concept of pathways.

It is indeed correct that there are some major channels that weave their way through the hurly-burly within cells, and among cells within organisms. But focusing solely on these major channels of biological causation would be like an attempt to understand the population and economy of Los Angeles in terms of its interstate freeways alone. Yes, cutting these freeways, or diverting them wholesale, has a major impact on the economy of the Southern California conurbation. But determining the impact of such wholesale disruptions is very different from a satisfactory analysis of the complexity of this urban region’s economy.

Thus, in developing a useful understanding of this complex three-dimensional web of cellular and organismal function, we need to use conceptual tools that are adequate to the task. Unfortunately, the reductionist toolkit of traditional 20th Century molecular and cell biology simply is not adequate, in strictly scientific terms. It isn’t just crude and mechanical. It is wrong.

Instead, we must look to such open-ended intellectual tools as population genetics, quantitative genetics, and systems biology to make sense of the explosive complexity of biological function. And such tools are inherently mathematical and computational.

9. The forces of natural selection weaken with adult age in species that have distinguishable adults and no fissile reproduction.

We now face the prospect of developing a 21st Century biology based on formal, mathematical, and computational tools. It is from this 21st Century biology that a new medicine for addressing our chronic health ailments will arise, those health ailments that are lumped together in medicine’s wastebasket called aging.

So, which formal, mathematical, and computational tools should we start with?

Many of the key applications of 20th Century physics grow out of its key equations. Atomic power and atomic bombs both grew out of Einstein’s result that E = mc2 . Television arises from the mathematics of the photoelectric effect, the result for which Einstein received the Nobel Prize. And so on.

Are there mathematical results of comparable significance for 21st Century biology and medicine?

Yes, there are. The first 8 of the 55 theses derive both directly and indirectly from basic quantitative results from evolutionary genetics. With this thesis 9, however, we come to the most important equations of all for the new medicine of chronic disease, those of Hamilton’s (1966) Forces of Natural Selection. In the references supplied with the 55, you can see the algebraic forms of the equations for these Forces, as well as graphical plots of them. But in these 55 theses, I will explain them in verbal terms for the mathphobic who have had their quantitative imaginations neglected or destroyed by their formal education.

Hamilton derived two Forces of Natural Selection in 1966. The first scales the impact of natural selection on the rate of mortality at each and every age, from birth to infinitely great ages. [Mortality refers to the probability of dying at a particular age.] The second scales the impact of natural selection on fecundity at each and every age, from birth to infinitely great ages. [Fecundity refers to the quantitative output of offspring at a particular age.] These two forces are among the most important formal results ever obtained by scientists.

10. When the forces of natural selection weaken with adult age, declining survival and fertility evolve in adulthood, and thus produce the decline in health which is commonly called ‘aging.’

In animals like mammals and insects, the Force of Natural Selection acting on mortality proportionately scales as follows. Childhood: From birth to the start of reproduction in a population, it acts with 100% of its maximum force. During this phase of life, therefore, natural selection acts strongly to sustain our inborn health, in terms of our capacity to survive, which can be thought of as our basic functional integrity. Even at full strength, natural selection won’t always succeed; accident, contagious disease, and mutation can all degrade health during the childhood years. But it does a damn good job. Aging Phase: From the earliest ages of reproduction until the last age of reproduction, the mortality force steadily declines. During this phase of life, natural selection progressively weakens its evolutionary surveillance of our health, resulting in predictable, general, and sustained declines in our health. Late-life Phase: After the last age of reproduction, and forever after, age-specific natural selection is gone. At this point, our health is sustained only by the age-independent health benefits built by natural selection for earlier ages. However, in many animal populations, this late-life phase features relatively reasonable health, and the preservation of some useful function, under protected conditions. But it does not among humans in industrial countries, an issue that we will discuss in detail later in the 55.

In animals like mammals and insects, the Force of Natural Selection acting on fecundity scales as follows. Childhood: From birth to the start of reproduction in a population, the fecundity force usually progressively falls. However, since we do not reproduce during this period, this has no observable effect. Aging Phase: During the earliest ages of reproduction, there is usually a transitional period during which fecundity increases rapidly with adult age. This can be thought of as the developmental result of all the quantitative effort that natural selection is putting into enabling the adult organism to develop the anatomical structures, physiological functions, and reproductive behaviors required for successful reproduction. Thus, in teen-aged humans, the first years of basic reproductive capacity are marked by relatively poor fertility, inappropriate or misdirected sexual behavior, and poor parenting behavior. But quickly, the adult human develops its full reproductive capacity, at around the age of 20 years in men, somewhat later in women. After that, fertility falls with age, the other side of declining health during adult life. Note that in mammalian species, which have a great deal of parental care of offspring, an infertile adult caring for their immediate offspring is still effectively reproducing. That is to say, in evolutionary terms female reproductive function extends past menopause. Late-life Phase: After the last age of survival in the evolutionary history of a population, age-specific natural selection for the maintenance of fecundity is gone. During this epoch of life, our reproductive functions are sustained only by age-independent benefits built by natural selection for earlier ages. However, in many animal populations, this late-life phase features measureable reproductive function. But it does not among humans in industrial countries, an issue that we will discuss in detail later in the 55.

11. If the forces of natural selection are strengthened during later adulthood, improved later health will evolve if natural selection is not impeded by very small population sizes, environmental change, or an absence of heritable variation.

There are a variety of ways to show that the Forces of Natural Selection provide the key factor in determining the evolution of the pattern of functional decline called aging. Some of them will be discussed in subsequent theses of the 55. But there is a strikingly simple pattern of comparative variation among different species of animal which makes the point fairly well, and you don’t need much biological background to understand it.

Consider turtles. Turtles come in very different shapes and sizes, some of which live out almost all their lives in oceans, like green sea turtles. Other types of turtle live in marshy wetlands. And we can consider tortoises, like the giant Galapagos Tortoises, as part of the overall turtle group, too. They almost never go swimming.

Some turtles and tortoises have very thick shells. Furthermore, many of them can retract their head and limbs inside these shells when they are attacked. Some of them, furthermore, have powerful biting mouths, which you would be ill-advised to place your fingers inside. When turtles and tortoises with these thick shells are maintained in zoos, they can live for very long periods of time, during which some of them maintain active sex lives. I have seen Galapagos tortoises at the San Diego zoo which are much older than I am, some probably at least 90 years of age. They still live with only modest medical care provided by their veterinarians.

On the other hand, soft-shelled turtles have much shorter lifespans, often less than twenty years, even when they are compared with hard-shelled turtles and tortoises of similar size. Why should this be so?

It is a basic feature of the Force of Natural Selection acting on mortality that a population which has suffered higher rates of mortality in its evolutionary history will tend to have its force decline faster with adult age, when everything else is equal. Soft-shelled turtles are not as good at defending themselves against predators as turtles with harder shells. Therefore, evolutionary theory predicts that they will evolve shorter lifespans, because of a faster decline in their forces of natural selection acting on mortality.

This concept readily generalizes to the following contrasts: similar species with and without venom, the venom giving better defense against potential predators, and the evolution of longer lifespans; similar species with and without flight, flight allowing ready escape from predators, and the evolution of longer lifespans; in general, larger animals are harder for predators to subdue and eat, so those species too tend to live longer. Sometimes multiple factors differ between species, such as larger snakes with no venom (like boid snakes) which may or may not live longer than smaller species with venom (like cobras). But when other factors are similar, an attribute that strongly reduces mortality levels will usually lead to the evolution of longer lifespans, when similar species are compared under good laboratory or zoo conditions.

12. Aging is a pattern of declining or de-tuned adaptation that is correlated with adult age only because adult age is at first strongly correlated with declining forces of natural selection.

We have all seen sunrise and sunset. In everyday language, we are describing a subjective experience of relative motion. But the sun doesn’t actually revolve around the Earth. It is just an optical illusion produced by the spinning Earth.

We have all seen the physiological deterioration of aging, or experienced it ourselves, which seems like a physiological process, akin perhaps to the filtering of our blood by our kidneys leading to their production of urine. Thus molecular and cellular biologists characterize aging in terms of hypothesized chronic physiological processes which are parallel to the production of urine. One of the most popularly hypothesized aging processes among such molecular biologists is free-radical damage, which non-biologists can think of as similar to rusting metal: progressive, cumulative, chemical damage involving oxidation.

In terms of the view articulated here, in the 55, this is as legitimate an inference as assuming that the sun revolves around the Earth. Aging seems exactly like cumulative damage, just like it seems to the uninformed that the sun revolves bout the Earth. Let me be clear. The Moon does orbit the Earth, as do many man-made satellites. You can suffer cumulative damage: your knee’s connective tissue will be progressively damaged if you repeatedly run marathons on pavement. So Earth-centered orbiting and cumulative damage are both processes that occur. The key scientific questions, though, are whether every celestial body orbits the Earth, and whether all the physiological impairments that accumulate during adulthood are due to cumulative damage. Most people know that the first hypothesis is false. Here the view is that the second hypothesis is also false.

We know why it seems as if the sun revolves about the Earth. It’s due to relative motion.

And some evolutionary biologists know why it seems as if aging is a process of cumulative chemical breakdown with adult age: Hamilton’s Forces of Natural Selection fall VERY predictably with adult age, ensuring that most animals will show palpable processes of deterioration. [The ones that don’t age effectively lack this fall in Hamilton’s Forces, for reasons we will discuss later.]

These conclusions don’t mean that there are no celestial orbits, or that there is no physiology involved in aging. A heliocentric solar system still has orbits, and the evolution of the aging still involves physiology. But aging is not a merely physiological, biochemically driven, process of cumulative damage. It is, instead, something else altogether. And the difference between these two views of aging is full of radical scientific consequences. And yet further, the difference between these two views of aging is fraught with still more radical medical implications.

13. The declining forces of natural selection lead to an evolutionary failure to establish the genomic information required for tuning the complex networks of life well enough to provide a high level of health indefinitely; there is no mechanistic necessity at the level of physiology to this failure.

It is intuitively hard for people who have never seen diagrams of solar systems to absorb the concept of a heliocentric solar system, in which the Moon orbits Earth, but Earth orbits the sun. But with such diagrams and a patient science teacher, most people get over the naturally-geocentric intuitive view.

It is still harder to get people to absorb the present-day Darwinian explanation of aging, as derived from Hamilton’s Forces of Natural Selection. I have been failing at this task for decades, and I am not alone. The problem is that the meaning of the equations and scientific diagrams that we use to explain the theory is not as intuitively accessible as diagrams of solar systems.

But I recently thought of another way to convey the idea. The key is to understand that animals and the cells that they are made from are extremely complex machines that function because of information stored in their genomes. That information is built by natural selection. When natural selection is impaired, by mutation or inbreeding for example, the information underlying function is degraded. That is, functional information from the genome is built by natural selection, to the extent to which natural selection can, given the evolutionary situation.

Some of this information is age-specific. So there is genetically encoded information that effectively “instructs” the mammalian fetus how to develop prior to birth. There is also genetically encoded information that effectively instructs the developing mammal to undergo a process of sexual maturation, in order to reproduce. All this information was produced in our evolutionary past thanks to the full force of natural selection acting at ages before the start of reproduction.

But natural selection has been under little pressure to specify instructions for useful function at later adult ages. It is not that there are material difficulties with sustaining life which natural selection cannot overcome; as we will discuss later in the 55, natural selection can easily do so. It is just that natural selection hasn’t bothered to develop the information for our indefinite survival. The information isn’t there. There is nothing to “read off” of the genome with which to sustain our youthful health. Those pages of our genomic instruction manual are either blank or defaced.

Unlike God in Woody Allen’s movie “Love and Death,” natural selection is not an underachiever when it comes to our aging. It just doesn’t care. Or you can think of it as a novelist or screenwriter who loses interest as they proceed through the drafting of their work. The last chapters just haven’t been written.

Physiologically, to the extent to which the genome doesn’t have useful instructions for later survival or fertility, it is going to become harder for the animals with that genome to survive or reproduce.

14. Aging hypotheses based solely on supposed universal imperfections of molecular, cell, or organismal physiology are wholly falsified by the existence of biological species that do not exhibit falling average rates of survival and reproduction among large cohorts maintained under good conditions, a pattern exhibited by some fissile coelenterates, for example.

But there is no need for a Darwinian biologist to be particularly eloquent about the falsity of conventional gerontological theories. The images of the round Earth supplied by the NASA Apollo missions that reached the Moon obviously annihilate Flat Earth theory. Likewise, evolution has supplied devastating refutations of the cumulative damage theories of mainstream aging research.

Those refutations are the animal species that don’t show aging. At all. It is now a well-demonstrated fact of aging research that there are some animals which do not show a detectable increase in rates of dying with time, even after decades of maintenance. Under the best conditions, when extremes of temperature and predation are entirely prevented, along with provision of good nutrition, some of these animal species which reproduce by splitting into similar offspring can apparently be kept alive indefinitely. For example, sea anemones are species that grow as circular tubes with fringe tentacles. Some of these species reproduce by longitudinally splitting their fully grown tubes to make two smaller tubes growing side-by-side. Then the smaller tubes grow as large as their mother, and split again themselves. Animals like these have been kept alive in aquaria, without a single one dying, over many decades. Sea anemones are species of the coelenterate group. Coelenterates that reproduce in this fissile manner only do not usually show aging. Other coelenterates that do not have any type of fissile reproduction do undergo aging.

This contrast is shown by other animal groups, such as some aquatic worms. Plants with extensive fissile reproduction, like trembling aspen trees, also do not show aging. There is nothing whatsoever in the basic cellular or organismal biology of animals and plants that requires aging. Evolution by natural selection can entirely eliminate aging, regardless of each and every feature of cumulative biochemical or other damage that whole organisms and their cells might be subject to.

Exactly why and how evolution is able to accomplish this feat is a matter we will take up later in the 55. But for now, I suggest that you contemplate a somewhat similar feat. Each and every one of us is a collection of somatic cells that have branched off from a lineage of germ-line, or reproductive, cells that has been maintained for hundreds of millions of years, since the origins of the first vertebrates about 500 million years ago. Evolution has apparently had little difficulty accomplishing this feat for vertebrates, crustaceans, and mollusks, all of which we find ancestors for among fossils dating back more than 500 million years before the present time.

That is, there is nothing about the indefinite maintenance of lineages of cells that evolution has any difficulty accomplishing. Rather, things become different when well-defined somatic cells are produced, cells that will not become part of offspring. The reasons for this lie in the circumstances under which the forces of natural selection do not decline, as will be explained further here in the 55.

15. Aging evolves because of the previously adduced evolutionary genetic limitations to the forces of natural selection, which are affected by physiology, but aging is nonetheless not a merely physiological process.

Do the last five theses imply that physiology does not matter? No, not at all. Physiological features of organisms matter a great deal for the evolution of their aging.

Both insects and mammals are thought to age universally. That is to say, no one has ever found an insect or mammalian species in which some part of adulthood is not marked by endogenous deterioration, regardless of how diligently they are cared for by their owners, zookeepers, or attentive laboratory scientists. When studied with enough care, all these species show some type of aging pattern that features both functional impairment and increased risk of death, along with declining reproduction in those species that reproduce more than once.

But is their physiology irrelevant? Insects and mammals differ significantly in their capacity to produce new cells as adults. Mammals have a great deal of cell proliferation as adults. Insects have fairly little, with most of this cell proliferation confined to their reproductive organs and their kidney-like organs, the Malpighian tubules. Mammalian aging often features an increased risk of cancer, a disorder of highly proliferative somatic cells. Insect aging rarely features cancer; insect cell proliferation is so stringently controlled in adults that very few aging insects have been found in which cancer is detectable. It happens, but without deliberately introducing mutations in a laboratory strain, insect cancer is very rare. Thus the cell biology of mammals and insects has material effects on their patterns of aging, including the presence or absence of cancer.

This example illustrates the point that the physiological features of a group of animal species affects how their aging evolves qualitatively. Previously, we have shown how other features of a group of species affects how their aging evolves quantitatively. Thus growing a shell, or not, strongly affects the evolution of aging. Some of the longest-lived animals are burrowing bivalves, which benefit from the protection of both their burrows and their shells.

One way to think of this relationship between aging and physiology would be as follows. Physiology at every level, from molecular biology to functional ecology, conditions the mortality risks and the patterns of reproduction of a species. These mortality risks and reproductive patterns determine the terms in the equations which define the Forces of Natural Selection. Those forces then condition the evolution of patterns of aging, subject to the availability of genetic variation, rates of mutation, and other evolutionary genetic factors. So physiology certainly conditions how evolution shapes aging. But it does not require, or by itself generate, aging.

16. Among the most important physiological constraints on the action of natural selection are trade-offs between the biological functions underlying age-specific rates of survival and reproduction.

One of the most important features of physiology that affects the evolution of aging is trade-offs between functions at early versus later ages. George C. Williams felt that this was the central requirement for the evolution of aging, as he argued in his famous 1957 paper on the topic. His conclusion was that, given his then-crude understanding of the declining Forces of Natural Selection, evolution would give up later deterioration for early vigor whenever it was given the chance.

There is a great deal of theoretical, comparative biological, and experimental evidence in favor of this hypothesis. Some of that evidence will be discussed in subsequent theses. But in this thesis the chief focus will be to develop the basic idea, particularly why so many biologists think that it is important.

The idea of evolutionary and functional trade-offs is one of the ubiquitous themes of biology. And it makes perfect sense in terms of physics and chemistry. Even in terms of engineering.

Think about automobiles. It would be very hard to build a car that can carry many passengers, get great gas mileage, and have outstanding acceleration or handling, all at the same time. There are material trade-offs that impinge on the automotive engineering of such a vehicle, where many of these constraints arise from basic features of physics, such as momentum and other corollaries of the laws of motion, as well as chemistry, such as the efficiency with which chemical combustion of gasoline can generate force.

In the same way, there are material constraints that affect how quickly a large animal can develop: how big it is at birth, how quickly it can be fed, how efficiently its food can be converted into growing tissue, and so on. Biology is full of constraints, some of which arise from basic features of physics and chemistry, some of which are more specifically biological, such as rates of cell division and the time required for cells to undergo differentiation.

Thus the basic concept of trade-offs can be naturally extended to relationships among such biological processes as survival and reproduction. An insect that provisions its eggs with fats from its abdominal fat body, and then lays those eggs and flies away, won’t have those fats with which to survive a subsequent period of starvation. It has used them up. It can get more nutrients, if it has mouthparts – which mayflies and some moths do not. But there is a material trade-off between resources sequestered for reproduction at early ages and resources conserved for survival to later ages. From this trade-off, as well as many other kinds of trade-off, the idea of a material antagonism between early reproduction and later survival is entirely natural.

17. When such trade-offs arise from antagonistic pleiotropic effects of genetic variants, they sometimes maintain genetic variation for functional characters, and thus selectable genetic variation for patterns of aging.

There are two kinds of trade-off which are important to distinguish when thinking about the evolution of aging: genetic trade-offs and non-genetic trade-offs.

Cases with genetic trade-offs are called antagonistic pleiotropy, a term I invented in the early 1980s. In genetics, the term pleiotropy refers to genetic variants which have multiple effects. With antagonistic pleiotropy, genes have variants with opposed effects on different components of fitness. Imagine, for example, an allele that gives rise to faster egg-laying in young adult insects, with the antagonistic pleiotropic effect of a reduced rate of adult survival thereafter. If the increase in early fecundity is large enough relative to the reduction in adult survival, natural selection will favor the genetic variants that sacrifice later survival for earlier reproduction.

This is where the Forces of Natural Selection have a critical role to play. The key factor is adult age. If the beneficial effect on reproduction is early in adulthood, but the adverse effect on survival is late in adulthood, the biased weightings of the Forces of Natural Selection in favor of early versus late ages strongly favor the evolution of increased early reproduction and decreased later survival. In this respect, natural selection plays the role of an unfair merchant, who tips the scale in favor of themselves when you aren’t looking. [That is why a Western symbol of Justice is a blind-folded woman holding up a pair of scales.] Natural selection is inherently biased in favor of early reproduction, all other things being equal.

There are three main possibilities for the evolution of genes that have antagonistic pleiotropy affecting aging. The first possibility is that survival costs of increased early reproduction are too great and too early relative to the benefits, and such genes will not spread by natural selection. The second possibility if that a gene gives rise to a significant net increase in fitness in every genotype in which it occurs. In such cases, natural selection will sweep genes like this to fixation if they arise with some frequency in a population.

The third possibility is that genes with antagonistic pleiotropy give some genotypes with increased fitness, but other genotypes with decreased fitness. In this case, such genetic variants first increase in frequency thanks to natural selection. But they do not sweep through populations all the way to fixation. They remain polymorphic, and can be detected in evolutionary and genetic experiments, revealing the antagonistic pleiotropic effect.

18 When such trade-offs can be physiologically tuned within the lives of individual organisms, natural selection may act to produce physiological machinery that provides plasticity which enhances average fitness.

One of the basic features of natural selection is its propensity to favor the exploitation of environmental contingencies. Thus, in the case of the lactose operon (an operon is a suite of bacterial genes located end-to-end) the genes for the digestion of lactose are “turned on” in the presence of lactose. Absent lactose, the enzymes that these genes produce are not produced in substantial quantities. But expose the bacteria to lactose, and its lactose operon responds by producing more transcripts of the genes for making the lactase enzyme. This is called phenotypic plasticity, where the term “phenotypic” indicates that it is not based on genetic change, and the term “plasticity” refers to change, not the involvement of carbon-based polymers that could be used to wrap food.

In cases of phenotypic plasticity like that of the lactose operon, evolution by natural selection is economizing on resources, where these resources may be material. Thus the resources involved in producing lactose-digesting enzymes include the nucleotides required to assemble the messenger RNA that carries the enzyme-building instructions from the genome. Then there are the amino acids required to assemble enzymatic protein, following the RNA-encoded instructions. There are the additional resources required to execute the protein synthesis process, such as the processing of the mRNA, the diversion of ribosomes to the task of assembling the required enzymes. Finally, there is just the metabolic time consumed with the task.

The term phenotypic plasticity is sometimes divided into two further subcategories: adaptive and non-adaptive. In the non-adaptive cases, there are no specific regulatory signals that modulate the phenotypic interactions between characters. Thus, for example, there is no specific regulatory signaling involved in the human body’s response to having a hand or a foot cut off. But there is definitely an extensive plastic response, as many other aspects of the phenotype respond to such dismemberment. With adaptive cases of phenotypic plasticity, there are hormones and other signaling agents involved in effecting a phenotypic change in response, where these signaling systems generally act to increase the average fitness of members of the population when it is kept in its ancestral conditions.

Note, however, that away from the environment in which those signals were established by natural selection, the effects of such signaling may be counter-productive. A favorite example of this for many of us who are interested in the human diet is our exaggerated and probably inappropriate appetite for sweetened foods, from ice cream to sodas. Basically, in our ancestral environments, we retained the general primate taste for sweet foods, perhaps because fruit consumption is such a widespread part of the primate diet. [Note that adult cats have no such “sweet tooth.” It is not inherent among all mammals.] But in our present industrial environment, in which food companies have an incentive to exploit every addictive or otherwise exaggerated preference for particular tastes, consuming “all the sweet stuff” leads many to lives of obesity, type II diabetes, and cardiovascular disease.

19. Such adaptive life-history plasticity will sometimes produce detectable trade-offs between survival and reproduction in the range of environmental conditions that prevailed when natural selection established such life-history plasticity.

It is a general, though not universal, rule that, if you give adult animals abundant nutrition, their fertility will increase. This is true in female insects and in female rodents. Among severely undernourished women, ovulation stops. Male mammals with inadequate nutrition have reduced fertility.

The interesting thing about such situations is that, in some species, this reduced reproduction is associated with increased capacities to survive, both under acute stress and over prolonged periods. This pattern has two interpretations: (i) the inevitable side-effect of reduced costs of reproduction; and (ii) an evolved life-history plasticity which enhances average fitness. Note, however, that these two explanations are not entirely opposed to each other. In some cases, animals may face unavoidable reductions in reproduction that then benefit survival, and yet they may evolve physiological mechanisms that strengthen this enhancement of survival under conditions of moderate deprivation.

But as with other instances of adaptive plasticity, adaptive life-history plasticity will be based on contingencies and constraints that were built in ancestral environment, not necessarily current ones. Thus the patterns of phenotypic plasticity that are found among laboratory animals living in environments that are evolutionarily novel to them will not necessarily reveal their benefits.

In exactly the same way, most humans now live in industrial environments that are evolutionarily novel to an extreme degree, particularly from the standpoints of nutrition and activity. Like most, but not all, animals, we are generally selected to economize on effort. Lions will sleep for many hours in a day, hunting only intermittently. On the other hand, many herbivores graze almost relentlessly during daylight. Apparently, bonobos in the wild also seek out food rather relentlessly. As omnivores, our behavioral inclinations toward activity are probably intermediate. But I wonder about the extent to which the slothful inactivity of the middle-aged on agricultural diets arises from inappropriate signaling. The middle-aged in hunter-gatherer tribes do not seem to be comparably lethargic.

20. A single pharmaceutical or nutritional substance will never cure aging, for aging is not a simple physiological disease or dysfunction, but the de-tuning of adaptation with adult age.

The quest for a substance that might arrest aging, or even reverse it, has been perennial. We have myths and records of this quest from both Eastern and Western Eurasian civilizations. Fountains of youth, philosopher’s stones, magic fruit or herbs that sustain youth, fortunate climes in which healthy centenarians live, they are all to be found in the written records of the great civilizations.

And these hopes and fables are still with us. The biotech company Geron was founded on the reductionist premise that determining how to give our somatic cells the capacity to remain “young” and proliferative would “cure the disease of aging.” Their focus was on the telomeres that are the caps to our chromosomes. As human cells divide under glass in laboratories where they can be kept alive outside of our bodies, their telomeres progressively shorten. When this shortening has largely eroded the telomeric caps, cell division slows and comes to a stop. Using this idea to “cure aging” is a bit more complex than a fountain of youth or the philosopher’s stone, but similar in its mythic aspirations.

Amazingly, in the 1990s, it proved possible to engineer human cells that produced enough telomerase to refurbish telomeres. The result, as the founders of Geron had hoped, was that these cells could proliferate indefinitely in human cells cultured under glass, with none of the slowing proliferation that was interpreted as “cell aging” for the last third of the 20th Century.

Geron’s attention then turned to identifying substances that might keep telomerase activated in the somatic cells of our bodies. And such substances have been found. For example, a component of the Chinese herb astragalus called “TA-65” is known to foster telomerase activity. TA-65 is now being marketed as a telomerase activator by a company called TA Sciences for use as a nutritional supplement to stave off aging, rather than a drug for a specific medical condition. There have been some promising clinical results from a double-blind placebo-controlled study of the effects of TA-65. Oprah Winfrey has been quoted as saying, “I want longer telomeres.” So is this the long-sought fountain of youth?

Telomerase activation exemplifies many of the difficulties with “solving the problem of aging” using the tools of molecular and cell biology. Malignant tumors have higher levels of telomerase activation, in most cases, than our normal somatic cells. This makes sense, in that cancer cells have relatively unbridled proliferation. Thus the problem for telomerase activation is that it is not necessarily good to have cells in our bodies with uncontrolled proliferation. Rather, the human body has multiple mechanisms, including telomere shortening, which actively forestall such cell proliferation.

More cell proliferation in our bodies is a double-edged sword. It would provide more cells with which to repair tissue damage, but it might put more of our cells on the road to becoming malignant. Finely tuned to target just those cells which would be most beneficial to keep proliferating, telomerase activation might be a useful therapy. But it is unlikely to alleviate all the things that go wrong in our bodies. And turning on cell proliferation generally might actually shorten life, by fostering cancer.

21. Multiple pharmaceutical substances or nutritional supplements will only ameliorate aging to the extent that they achieve genome-wide tuning similar to that which natural selection achieves when its forces are strengthened at later ages.

So how best to use the range of candidate anti-aging substances? It is not my view that such substances should never be used. There is nothing magical, on my view, about aging. It is a result of evolution by natural selection failing to provide the physiological machinery that could indefinitely sustain the lives, and thus health, of organisms. When evolution builds organisms that can live indefinitely, it does so using perfectly ordinary biochemical machinery. In principle, there is no reason why biological science cannot emulate this feat, supplying similar machinery to keep humans alive indefinitely.

The challenge is that when natural selection builds the adaptations that sustain health, it uses quite complex biochemical machinery. This biochemical machinery is certainly not intelligently designed, because evolution always builds adaptations based on preexisting features of organisms. Evolution can’t start with a blank sheet, and make elegant design decisions. The more you learn about how organisms function, from the visible machinery of organs and tissues down to the processing of individual molecules, the more you will see what a patched-together contraption your body is.

But that patching-together, that progressive tinkering, proceeds by fine-tuning hundreds of biochemical pathways in concert, not one or two. Thus the problem of intervening in the tuning of adaptation with adult age necessarily involves emulating what natural selection can accomplish. Such “anti-aging” intervention might not have to be quite as complicated as what evolution does, but it would have to be comparable in appropriateness and utility.

Thus radical anti-aging intervention requires acquiring a great deal of information about how our genomes tune our health as a first step. Then the goal would be to change that tuning so that health can be sustained. While this might seem to be a virtually impossible task, there are research strategies that can disclose how this should be done, research strategies that we will be reviewing later in the 55.

For now, it is important to keep firmly in mind that, whatever our hopes or fears, aging is not a simple problem at the level of physiology. It is instead an extremely complex problem. It is only simple from the standpoint of evolutionary theory, as I have outlined, and, as we will discuss, evolutionary experimentation.

22. Repairing molecular or cellular damage will provide at most partial amelioration for the problem of de-tuned adaptation with adult age, because cumulative damage will also occur at organ and systemic levels at every physiological level as a result of the de-tuning of adaptation with age.

One of the basic theories of aging that has enjoyed popularity among cell and molecular biologists is that aging is due to cumulative damage at the cellular and molecular level. Taking this particular reductionist theory as gospel, the charismatic Aubrey de Grey has proposed that we can solve the problem of aging simply by repairing all such damage. In his somewhat Panglossian view, there are only seven types of cell/molecular damage, and there are relatively straightforward ways to repair that damage, he says. On the basis of this line of reasoning, de Grey expects that a sufficiently concerted research effort should be able to overcome aging within the next thirty to fifty years.

Even if we take this “aging is cumulative damage” theory on its own terms, well-trained pathologists would naturally point out that cumulative damage can also occur at the organ and systemic levels. Those addicted to running assiduously pound away on their joints if they run regularly on concrete and other paved surfaces. After the early twenties, our joints no longer re-grow cartilage, so such running can literally wear-away the connective tissue that sustains joint function, progressively hobbling us. The acids in our stomach frequently reflux up into our esophagi, eating away at their tissues, leading to degraded esophageal function, which we experience as heartburn and difficulty swallowing. And this list goes on.

Damage occurs at every level of our bodily machinery. Yes, it always involves changes to molecules and cells, but the causes of cumulative damage are not confined to those levels. Furthermore, the widespread turnover of cells and molecules throughout much of the human body suggests that our bodies already have fairly good machinery for dealing with damage at these lower levels: get rid of damaged cells and replace them with new ones that have not yet been damaged.

Thus, even on their own terms, molecular damage theories of aging do not necessarily lead to elegant technological solutions to the problems of aging, because there are many types of damage that may require repair, some well above the level of individual cells functioning in isolation.

23. Repairing all types of cumulative damage during the aging phase will provide at most partial amelioration for the problem of declining adaptation with age, because some of this decline will be due to failures of signaling and other features of gene regulation as a result of the de-tuning of adaptation with age.

The functioning of cells as complex as those of humans involves much more than the repetitious execution of the same biochemical processes over and over again. Rather, our cells have elaborate networks of interaction among proteins and the nucleic acids involved in their synthesis. Among the specific agents involved in these complex networks are transcription factors, proteins that affect the production of other proteins, sometimes on a vast scale, with one transcription factor affecting the production of hundreds of different types of protein.

This coordination of function by cells involves intracellular signaling cascades and other information-laden patterns of coordination. In a sense, the human cell is a spectacularly complex hybrid analog-digital computer, where the digital components are provided by the nucleic acids, and the analog components are the proteins. At ages when natural selection is acting with its full power, what our cells can accomplish is remarkable with respect to efficiency and precision. But with an evolutionary view of health and function like the present one, as the forces of natural selection fade with adult age, the control of our cell functions is expected to deteriorate. Thus, we can expect that some of our cells will become so dysfunctionally regulated with age as to turn malignant, losing self-inhibitory mechanisms, and degenerating into highly proliferative rogue cells that engender cancer, to give just one example.

It is not the case that, during aging, perfectly and perpetually attuned cells progressively lose function solely because of a substratum of damaged molecular components. In addition to any such damage, the evolutionary genetic tuning required to sustain the signaling systems of the human cell will not be there at later ages. Metaphorically, it is not just that the car is rusting; the driver is also falling asleep. The cell genome is running out of information with which to sustain its role at later ages. There are any number of metaphors that could be used here: an actor who has run out of script; a videogame that hasn’t been properly programmed for its later “levels;” driving away from a city and having its radio stations fade out; and so on.

Thus, whatever damage we are able to repair at the level of cell, there will still be failures of function arising from progressively more severe failures of coordination among the complex networks that sustain cell functions.

24. Altering all cell-molecular regulatory signaling during the aging phase will provide at most partial amelioration for the problem of declining adaptation, because dysfunctional signaling will also arise at organ and systemic levels as a result of the de-tuning of adaptation with age.

The functioning of a whole organism as complex as a human involves much more than the repetitious execution of the same processes over and over again. Rather, our physiology involves a number of signaling pathways among tissues and organs, from the slower hormonal signals to the rapid electrical signal transmission carried out by neurological tissue.

At the peak of adaptation, just prior to the onset of reproduction in an evolving population, this coordination of function by signaling is amazingly proficient. Thus we have the thirteen year-olds with an amazing ability to acquire random new information, whether from friends, the internet, or even their teachers. But with an evolutionary view of health and function like the present one, these gifts are the predictable effect of natural selection operating at full power.

Conversely, as the forces of natural selection fade with adult age, our mental facility and our physiological responsiveness deteriorate. This deterioration is masked in humans by the accumulated intellectual capital and skills that we have acquired thanks to our earlier proficiency at signaling, coordination of functions, and marshalling of resources. Older professors usually know more than beginning graduate students, and veteran athletes know the tricks of the game that the upcoming rookies are just learning. But the reaction times of the professors and the veteran athletes will generally be slower than those of their younger colleagues.

It is not the case that, during aging, a perfectly attuned organism progressively loses function solely because of a substratum of progressively damaged cells or organs. In addition to any such damage, the evolutionary genetic tuning required to sustain the signaling systems of the human body will not be there at later ages. Again, it is not just that the car is rusting; the driver is also falling asleep. To suppose otherwise requires a resort to a Cartesian dualism in which “the mind” and other coordination functions come from another realm, one that is not subject to the lack of information that afflicts the body, considered as an inert aggregate of cells. And I reject any such Cartesian dualism, as I suppose most modern biologists must.

Thus, whatever damage we are able to repair at the level of cell or organ, there will still be failures of function arising from progressively more severe failures of coordination among tissues and organs. Perhaps a useful metaphor for this would the American Congress, which features a lack of coordination that can boggle the mind of the uninformed American voter or the visitor from a country that has a rational legislative system, particularly one not designed to thwart cogent and expeditious policy.

25. Repairing all forms of cumulative damage and altering all types of regulatory signaling during the aging phase will also fail to fully alleviate aging, because some features of aging will arise from the absence of structural gene-products required to sustain health indefinitely during adulthood as a result of the de-tuning of adaptation with age.

But not all failures of adaptation at later adult ages will be due to damage or poor coordination. Sometimes the endogenous deaths of adults arise from the absence of necessary bits of machinery, from the level of the cell to that of the entire organism.

It is at the level of the whole organism that this failure of evolution to supply “missing parts” is most obvious. The rapidly deteriorating adult mayfly lacks mouthparts. Its sole role as an adult is to find a mate, copulate, and, if female, deposit its eggs appropriately. This is also true of many moth species, which also entirely lack functional mouths as adults. Evolution’s failure to sustain mouths in some adult insects is a fairly extreme failure to supply a part whose lack dooms them to deterioration and an early death.

With somewhat greater subtlety, vertebrates vary widely in the availability of replacement teeth. Humans get just two sets in their lives. Elephants get six. But in either case, absent dentistry, once we have lost too many of our ultimate set of teeth, our subsequent nutrition will be impaired.

By this same biological logic, there is no reason for natural selection to supply our cells with enzymes that might catalytically prevent or repair sundry types of damage or dysregulation at indefinitely great ages with full efficacy. Evolution will produce biochemical bits of cell machinery that sustain function at every age, if there is no trade-off or separation between these functions at different ages. Worse still, if evolution by natural selection faces a trade-off between earlier and more prolific reproduction and the provision of missing components that might sustain life indefinitely, the declining forces of natural selection combined with this antagonistic pleiotropy will ensure that the later adult will be missing key features required to sustain life infinitely.

26. The forces of natural selection can be strengthened during adulthood by postponing the first age at which they begin to decline, which can be achieved for the force of natural selection acting on age-specific mortality by postponing the first age of reproduction.

Much of the first 25 theses focused on problems with prevailing views. That is, in large measure, to this point I have been setting about the destruction of conventional views concerning aging and the foundations of health, views that dominate Western medical thinking about medicine and cognate health issues.

But this would not be a very useful effort if it were little more than a critique of existing medical or gerontological thinking. Starting with this thesis 26, I will be setting out a positive alternative program, a set of ideas about experiments and health practices that can make a constructive difference to patterns of aging.

Let’s start with the first important idea I had as an experimentalist, in the fall of 1977. That was when I realized that the natural selection might quickly retune aging if it was artificially strengthened at later adult ages. A key parameter affecting the force of natural selection acting on survival is the first age at which a population begins to contribute offspring to the next generation. This parameter is conventionally labeled b.

Basically, the force of natural selection acting on survival is weighted according to the proportion of a population’s reproduction that lies in its future. By increasing the value of b in an experimental context, one would be strengthening the force of natural selection at all ages between the previous value of b and its new higher value. As a matter of biological practice, b can be shifted upward to a much higher value so long as there are enough fertile survivors available after the new first age of reproduction.

This was simple mathematics. But what remained unaddressed in 1977 was whether or not there would be enough standing genetic variation, or “heritability” in the language of quantitative genetics, for natural selection to respond quickly to this shift in the force of natural selection. At that time, we did not know how common such genetic variation was among outbred populations. In particular, many biologists, even evolutionary biologists, thought that genetic variation affecting characters like survival was pretty thin on the ground. That was because they were still thinking in terms of evolution in terms of intermittent, rare, beneficial genes arising by mutation and sweeping toward fixation.

A simple way to understand my career, and my reputation as a scientific rebel – if not rapscallion, is that my success as a scientist has been based on repeatedly betting against conventional wisdom. At times, when I have bet against the conventional wisdom, I was betting against the very beliefs that I had been inculcated in during my training. Thus, I was often betting against assumptions that I myself cherished, and might have been as unable to question as anybody else just weeks or months before.

27. Among populations which have had their forces of natural selection strengthened experimentally, detectable improvements in adult survival and reproduction have been observably achieved within dozens of generations.

So there I am, in 1977, realizing that all evolution has to do to postpone aging is have its force of natural selection strengthened during adulthood by shifting the age of first reproduction. What was not clear then was whether or not it could do so quickly.

The experimental material I used to test this idea was a laboratory population of the fruit fly, Drosophila melanogaster, which I was maintaining at moderate populations sizes of around 1,000 to 2,000 individuals. Would this population have the genetic variation I needed to test the idea of slowing aging by shifting the age at which natural selection would start to fail?

At that time, I was engaged in laboriously testing that population for its quantitative genetic variation. But I wouldn’t get all the results I needed for another 16-18 months. So, impetuously, I just gambled that it would be there. Fortunately, my advisor was away for the year, and couldn’t talk me out of this plan. Nor did I have to appeal to a “better not” grant-review panel.

I took that fruit fly population and split it into controls, which were reproduced at 14 days of age from when they were eggs, and an experimental population, which reproduced at 35 days of age. I then maintained these two populations like this for a dozen generations of late-reproducing flies, about a year. Then I reared them in parallel, and observed their pattern of reproduction and survival as adults.

The results were that the population with postponed first reproduction, an increased b in Hamilton’s terminology, had a significantly increased average lifespan and a shift of reproduction from early to later ages. That is, my bet had worked. In only a year, my delayed-reproduction fruit flies had their pattern of aging evolutionarily shifted toward slowed aging.

Since then, this experiment has been repeated many times by myself and others, with fruit flies, other insects, and even mice, and the results have been qualitatively consistent. Shifting the first age of reproduction upward quickly results in the evolution of increased lifespan and somewhat slower aging. Even with the bad technique that prevails in most biological laboratories, this experiment is easily done, and the results are predictable.

This was the experimental breakthrough that has served as a crack in the edifice of conventional theories of aging, a crack through which the waters of scientific change have seeped ever since. The journals and the grant-reviewing panels have mightily resisted this scientific change, as we can expect that they always will resist substantive reform of conventional views. But the power of strong-inference science cannot be resisted forever, not even by biologists and physicians, as those of us who are the scientific descendants of Charles Darwin know well. We evolutionary biologists all grow up intellectually on tales of the obdurate stupidity of scientific establishments.

28. Among such experimental populations evolving greater levels of adaptation at later adult ages, evolutionary changes in (a) structural gene frequency, (b) gene regulation, (c) patterns of cumulative damage, and (d) still other features of physiological function will reveal the mechanistic changes required to enhance adaptation at later ages in that species, and thereby ameliorate its aging.

Laboratory populations that have evolved greater levels of adaptation, and thus prolonged survival, during adulthood are key material for unraveling the conundrums of aging. If the views articulated here were NOT correct, it wouldn’t be possible for experimental evolution to turn aging around on a dime by delaying the decline in the forces of natural selection. Instead, the nostrums of molecular biologists would readily and easily postpone aging. But they don’t. Thus biomedical research on aging should focus on what evolution does when it slows or postpones aging.

So there now exist material embodiments of re-tuned aging: Methuselah Flies that have much greater lifespans, both average and “maximum” (where the definition of the latter is a problem that we will discuss later in the 55), as well as better sustained fertility. As such, we can directly examine just what it takes to re-tune aging, at every level: genetic, biochemical, molecular, cellular, organ, and whole-organism.

My laboratory has already released an entire book on the experimental characterization of how these Methuselah Flies are able to live and function longer (Methuselah Flies, 2004; Rose, Passananti, & Matos, eds.; World Scientific). That would be the work to read for an introduction to these flies.

But let me give a crude overview of what longer-lived, longer-reproducing, fruit flies are like. They have changes at many genetic sites distributed throughout their genomes, NOT changes at just a few genes. This means that genetically engineering or pharmaceutically manipulating human biochemistry to achieve radically greater lifespans is not going to be a feasible project. There are too many targets Instead, our physiologies have to be re-tuned at many levels, and in complex ways.

Some of this physiological complexity is starting to emerge from careful work on fruit flies with improved aging. Here are some characteristic features of longer-lived fruit flies: greater resistance to acute stress, greater physiological reserves, normal metabolic rates, better maintenance of physical activity, greater athletic endurance, greater reproductive restraint under bad conditions, and so on.

A number of molecular biological hypotheses about aging have been tested in these flies. While the failures to corroborate these institutionally favored hypotheses have consistently NOT been published, because at least some molecular and cell biologists exhibit little commitment to strong-inference science, I can tell you that there is significant unpublished research on these flies which falsifies favored reductionist hypotheses. To a first approximation, it would be fair to say that these flies have served as a nemesis for conventional molecular and cellular theories of aging. Overall, the reductionist theories of aging appear to be systematically worthless, of no better than incidental validity, from the evidence of experimental evolution. Which is just as evolutionary theory suggests they should be.

29. Species with fully symmetrical fission as the sole means of reproduction do not have a declining force of natural selection acting on survival, and they do not evolve aging phases in which all individuals show declining survival.

I have already mentioned that there are organisms that show no signs of aging, not even when they are carefully maintained in scientific laboratories. Some of these are multicellular animals that have eukaryotic cells very similar to our own. Yet, no aging. Ergo, aging cannot be due to features of cell biology that are common among animals.

It is not trivial which animal species evolve to be free from aging. These are all species in which the Forces of Natural Selection do not decline, as is to be expected in the evolutionary theory of aging.

Under what conditions is such decline prevented? As already mentioned, non-aging species reproduce by splitting into similar offspring, only. Coelenterates that reproduce in this fissile manner only do not usually show aging. Other coelenterates that do not have any type of fissile reproduction do undergo aging.

The fundamental determinant of aging is whether the Forces of Natural Selection decline with adult age or not, rather than the biological details. If an organism develops to the point of reproduction, and then reproduction leads to two symmetrical “newborns,” there is no opportunity for the Forces of Natural Selection to fall, because there is no adult organism at all. There are only juveniles.

As the Methuselah Flies also suggest, the straightforward evolutionary explanation of the existence of non-aging animals brutally demonstrates the vacuity and irrelevance of the cell-molecular approach to aging, the overwhelmingly dominant biomedical research paradigm in aging and biomedical research.

More generally, it also suggests the vacuity and impotence of the cell-molecular paradigm for systematic progress in addressing most of the key chronic diseases which are devastating millions of people in industrial countries. Cell and molecular biologists will certainly generate many publications as they study such chronic diseases. And they will award each other numerous research grants, get their protégés good tenured faculty jobs, etc. But millions of patients will suffer and die for the scientific and technological inadequacy of the prevailing cell-molecular dogmas. This seems like a high price to pay for continuing to support a biomedical priesthood that chooses to overlook the limits to their knowledge, sometimes willfully.

If Martin Luther was so outraged by the excesses of the Catholic hierarchy that he posted 95 theses on a cathedral door, my 55 theses reflect a still greater outrage over the millions that are now suffering and dying in order that the present-day complacency of the biomedical establishment, and its allies in the pharmaceutical industry, be maintained without challenge.

30. The forces of natural selection plateau at zero values at very late adult ages, and do not decline further for all subsequent ages.

This is the most important thing of all, even if no one understood what it means for human health for decades. The point is this. Aging is merely the de-tuning of adaptation during adulthood, not a physiological process. This de-tuning arises from the falling forces of natural selection. Ergo, if these forces stop falling, then the de-tuning of adaptation should stop too. This means aging can stop.

Thus the point that the forces of natural selection stop falling is key to everything that follows in the present re-visioning of the prospects for human health. So you need to pay careful attention to this point, because it has the potential to change the lives of billions of people.

A brief detour into the history of physics is possibly instructive, even though I am not expecting you to worry about the details of the physics involved. The hallmark of real science, as opposed to the trivia of natural history and cell biology, is that its equations can have spectacular consequences. Thus the apparently simple equation E = mc2 is one of the most practically important results in all of science, for the following reasons. It gives the relationship between mass (m) and energy (E), when mass is converted into energy. Little noticed by most people, who aren’t physicists after all, is the c2 term. The symbol c in physics stands for the speed of light, which is a very big number. Square it (multiplying it by itself) and you get an even bigger number. This t