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Is your life span broken?

August 21, 2009

Aging is controlled by genes and the environment, and poses the largest single risk for developing a panoply of diseases, including cancer. Why do organisms age, and why do diseases such as cancer rise exponentially with age? My laboratory aims to understand the molecular and cellular basis of aging in mammals.

– Judy Campisi, Ph.D.

I recently attended the BioScience Forum, at which Judy presented “Curing Aging: A Mad Pursuit?”  [See her Nature article posted in the comments.]  While others may have said the same things in a depressed tone, Judy spoke with passion about the problems confronting aging research.  She clearly has no intention of giving up.  Judy is quite a remarkable lady.

The broad points of her talk:

  • Can we extend life? Yes, of course – we already have!  We’ve doubled our “pre-cell phone” lifespans, primarily by controlling our environments.
  • We have increased our lifespans more quickly than our genomes can adapt to compensate. We may be able to extend lifespan further (specific approaches in the paper), but we would continue to age.
  • To combat aging due to the accumulation of damage, we can remove the accumulation, allowing us to continue functioning healthfully into advanced age.

Judy and collaborator, Jan Vijg, were recently mentioned in the New York Times article, “Tests Begin on Drugs That May Slow Aging.” [Full text in comments.]

The article raises whether supplementation with certain chemicals can extend life. Perhaps, is the answer, though it does lean positively toward the notion that lifespan can be extended through currently available commercial chemical intervention. Interestingly, Judy’s research is used to support the less hopeful side of the argument.  This seems a case of a carefully worded academic paper causing diminished expectations of future therapies. (A bigger issue that greatly bothers me.)

The article ends with a mention that life span is not fixed. I couldn’t understand what that meant… But, semantics aside, the important point is that the author implies that aging is a problem.

– – –

Aging is a puzzle to be solved by people.  Single individuals can have a great impact in this field.  Simply by considering the belief that death is not inevitable, a paradigm shift occurs.  We don’t have to die.  OK.  Now the choice: do you want to live or do you want to die?  Let’s assume – dear, animate reader – that you and me and we want to live.  What can we do?  I encourage you to think about this.

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  1. August 21, 2009 2:41 PM

    Tests Begin on Drugs That May Slow Aging

    By NICHOLAS WADE
    Published: August 17, 2009

    It may be the ultimate free lunch — how to reap all the advantages of a calorically restricted diet, including freedom from disease and an extended healthy life span, without eating one fewer calorie. Just take a drug that tricks the body into thinking it’s on such a diet.

    It sounds too good to be true, and maybe it is. Yet such drugs are now in clinical trials. Even if they should fail, as most candidate drugs do, their development represents a new optimism among research biologists that aging is not immutable, that the body has resources that can be mobilized into resisting disease and averting the adversities of old age.

    This optimism, however, is not fully shared. Evolutionary biologists, the experts on the theory of aging, have strong reasons to suppose that human life span cannot be altered in any quick and easy way. But they have been confounded by experiments with small laboratory animals, like roundworms, fruit flies and mice. In all these species, the change of single genes has brought noticeable increases in life span.

    With theorists’ and their gloomy predictions cast in the shade, at least for the time being, experimental biologists are pushing confidently into the tangle of linkages that evolution has woven among food intake, fertility and life span. “My rule of thumb is to ignore the evolutionary biologists — they’re constantly telling you what you can’t think,” Gary Ruvkun of the Massachusetts General Hospital remarked this June after making an unusual discovery about longevity.

    Excitement among researchers on aging has picked up in the last few years with the apparent convergence of two lines of inquiry: single gene changes and the diet known as caloric restriction.

    In caloric restriction, mice are kept on a diet that is healthy but has 30 percent fewer calories than a normal diet. The mice live 30 or 40 percent longer than usual with the only evident penalty being that they are less fertile.

    People find it almost impossible to maintain such a diet, so this recipe for longevity remained a scientific curiosity for many decades. Then came the discovery of the single gene changes, many of which are involved in the body’s regulation of growth, energy metabolism and reproduction. The single gene changes thus seem to be pointing to the same biochemical pathways through which caloric restriction extends life span.

    If biologists could only identify these pathways, it might be possible to develop drugs that would trigger them. Such drugs could in principle have far-reaching effects. Mice on caloric restriction seem protected from degenerative disease, which may be why they live longer. A single drug that protected against some or all the degenerative diseases of aging would enable people to enjoy more healthy years, a great benefit in itself, even if it did not extend life span.

    The leading candidates for such a role are drugs called sirtuin activators, which may well be mimicking caloric restriction, in whole or in part. The chief such drug is resveratrol, a minor ingredient of grapes and red wine. Sirtris Pharmaceuticals, of Cambridge, Mass., is now conducting clinical trials of resveratrol, in a special formulation, and of small-molecule drugs that also activate sirtuin but can be given in much lower doses. The resveratrol formulation and one of the small chemicals have passed safety tests and are now being tested against diabetes and other diseases. The Food and Drug Administration does not approve drugs to delay aging, because aging in its view is not a disease.

    The sirtuin activators have a strong scientific pedigree. They emerged as the surprising outcome of a quest begun in 1991 by Leonard P. Guarente of M.I.T. to look for genes that might prolong life span in yeast, a single-cell organism. Working with David A. Sinclair, now at Harvard Medical School, he discovered such a gene, one called sir-2. People and mice turned out to have equivalent genes, called sirt genes, that produce proteins called sirtuins.

    Dr. Guarente then found that the sirtuins can detect the energy reserves in a cell and are activated when reserves are low, just what would be needed for a protein that mediates the effects of caloric restriction. Dr. Sinclair and colleagues screened a number of chemicals for their ability to activate sirtuin, and resveratrol landed at the top of the list. The chemical was already known as the suspected cause of the French paradox, the fact that the French eat a high fat diet without penalty to their longevity.

    The two researchers and their colleagues thus argued that caloric restriction works by activating sirtuins, and so drugs that activate sirtuins should offer the same health benefits.

    In 2004 Dr. Sinclair co-founded Sirtris with Christoph Westphal, a scientific entrepreneur. Helped by growing interest in the sirtuin story, Dr. Westphal was able to sell the company last year to GlaxoSmithKline for $720 million.

    Dr. Sinclair says that “the results from the Sirtris compounds are promising and will be submitted for publication in coming months.”

    But despite the high promise and strong scientific foundation of the sirtuin approach, it has yet to be proved that Sirtris’s drugs will work. The first of many questions is that of whether caloric restriction applies at all to people.

    Two experts on aging, Jan Vijg of the Albert Einstein College of Medicine and Judith Campisi of the Lawrence Berkeley National Laboratory, argued recently in Nature that the whole phenomenon of caloric restriction may be a misleading result unwittingly produced in laboratory mice. The mice are selected for quick breeding and fed on rich diets. A low-calorie diet could be much closer to the diet that mice are adapted to in the wild, and therefore it could extend life simply because it is much healthier for them.

    “Life extension in model organisms may be an artifact to some extent,” they wrote. To the extent caloric restriction works at all, it may have a bigger impact in short-lived organisms that do not have to worry about cancer than in humans. Thus the hope of mimicking caloric restriction with drugs “may be an illusion,” they write.

    To decide whether life extension by caloric restriction is an artifact of mice in captivity, why not try it on wild mice? Just such an experiment has been done by Steven N. Austad of the University of Texas Health Science Center. Dr. Austad reported that caloric restriction did not extend the average life span of wild mice, suggesting the diet’s benefits are indeed an artifact of mice in captivity. But others interpret his results differently. Richard A. Miller of the University of Michigan, says the maximum life span of the wild mice was extended, and so the experiment was a success for caloric restriction.

    Laboratory mice are very inbred, and researchers can get different results depending on the breed they use. To put the mouse data on a firmer footing, the National Institute on Aging has set up a program to test substances in three labs simultaneously. Its first round of candidate agents for reversing aging include green tea extract and two doses of resveratrol.

    The resveratrol tests are still under way, but last month the results with another substance, the antifungal drug rapamycin, were published. Rapamycin was found to extend mice’s lives significantly even though by accident the mice were already the equivalent of 60 years old when the experiment started.

    Rapamycin has nothing to do with caloric restriction, so far as is known, but the study provided striking proof that a chemical can extend life span.

    Another result, directly related to the caloric restriction approach, emerged last month from a long-awaited study of rhesus monkeys kept on such a diet. The research was led by Richard Weindruch of the University of Wisconsin. As fellow primates, the monkeys are the best possible guide to whether the mouse results will apply in people. And the answer they gave was ambiguous.

    The monkeys who had spent 20 years on caloric restriction were in better health than their normally fed counterparts, and suffered less diabetes, cancer and heart disease, apparently confirming that caloric restriction holds off the degenerative diseases of aging in primates as well as rodents.

    But as for life span, the diet extended life significantly only if the researchers excluded deaths that were apparently unrelated to aging, such as under the anesthesia necessary to take blood samples. When all deaths were counted, life span was not significantly extended.

    Some researchers think it is perfectly valid to ignore such deaths. Others note that in mouse studies one just counts the numbers of dead mice without asking what they died of, and the same procedure should be followed with monkeys, since one cannot be sure if a death under anesthesia might have been age related.

    With the rapamycin and rhesus monkey results, Dr. Sinclair said, “We have more weight on the side of people who think it’s going to be possible.” He stressed the ability of both caloric restriction and sirtuin-activating drugs to postpone the many diseases of aging, at least in mice. To have one drug that postponed many degenerative diseases in people would be a significant advance, he said, even without any increase in longevity.

    People may live so long already that no drug could make much of a difference. Probably because of reductions in infant mortality and other types of disease, human life expectancy in developed countries has been on a remarkable, unbroken upward trend for the last 160 years. Female life expectancy at birth rose from 45 years in 1840 to 85 years in 2000.

    An important difference among experts on aging is whether there is an intrinsic rate of aging. Supposing there were cures for all diseases, what would one die of, if one died at all? Dr. Vijg and Dr. Campisi believe there is a steady buildup of damage to DNA and to proteins like the collagen and elastin fibers that knit the body together. Damage to DNA means that the regulation of genes gets less precise, and this regulatory drift disrupts the stem cells that repair each tissue. Even if all disease could be treated, it is not clear that anything could overcome intrinsic aging.

    Dr. Miller, on the other hand, believes no clear distinction can be made between disease and other frailties of aging. “Anything a doctor can charge for we call disease, but wrinkled skin, white hair or not feeling good in the morning, these we don’t call disease,” he said.

    He thinks that the idea of intrinsic aging is not well defined and that contrary to the theories of the evolutionary biologists, there may be simple ways to intervene in the aging process.

    In the view of evolutionary biologists, the life span of each species is adapted to the nature of its environment. Mice live at most a year in the wild because owls, cats and freezing to death are such frequent hazards. Mice with genes that allow longer life can rarely be favored by natural selection. Rather, the mice that leave the most progeny are those that devote resources to breeding at as early an age as possible.

    According to this theory, if mice had wings and could escape their usual predators, natural selection ought to favor longer life. And indeed the maximum life span of bats is 3.5 times greater than flightless mammals of the same size, according to research by Gerald S. Wilkinson of the University of Maryland.

    In this view, cells are so robust that they do not limit life span. Instead the problem, especially for longer-lived species, is to keep them under control lest they cause cancer. Cells have not blocked the evolution of extremely long life spans, like that of the bristlecone pine, which lives 5,000 years, or certain deep sea corals, whose age has been found to exceed 4,000 years.

    Some species seem to be imperishable. A tiny freshwater animal known as a hydra can regenerate itself from almost any part of its body, apparently because it makes no distinction between its germ cells and its ordinary body cells. In people the germ cells, the egg and sperm, do not age; babies are born equally young, whatever the age of their parents. The genesis of aging was the division of labor in the first multicellular animals between the germ cells and the body cells.

    That division put the role of maintaining the species on the germ cells and left the body cells free to become specialized, like neurons or skin cells. But in doing so the body cells made themselves disposable. The reason we die, in the view of Thomas Kirkwood, an expert on the theory of aging, is that constant effort is required to keep the body cells going. “This, in the long run, is unwarranted — in terms of natural selection, there are more important things to do,” he writes.

    All that seems clear about life span is that it is not fixed. And if it is not fixed, there may indeed be ways to extend it.

  2. August 21, 2009 2:44 PM

    Review

    Nature 454, 1065-1071 (28 August 2008) | doi:10.1038/nature07216

    Puzzles, promises and a cure for ageing

    Jan Vijg1,3 & Judith Campisi1,2
    Top of page
    Abstract

    Recent discoveries in the science of ageing indicate that lifespan in model organisms such as yeast, nematodes, flies and mice is plastic and can be manipulated by genetic, nutritional or pharmacological intervention. A better understanding of the targets of such interventions, as well as the proximate causes of ageing-related degeneration and disease, is essential before we can evaluate if abrogation of human senescence is a realistic prospect.

    The inevitability of ageing and death has preoccupied humanity for more than 5,000 years. In the epic named after him, Gilgamesh, the Sumerian king of Uruk, seeks to escape death, but ultimately concludes this is futile and turns to lasting works of culture to achieve immortality. Nowadays, disease—not death and the opposite, eternal life—preoccupies most biomedical scientists. Nevertheless, advances in understanding basic ageing mechanisms have made it difficult to ignore the issue of whether biomedical interventions to postpone ageing substantially are scientifically plausible. The overarching question is not whether mean human lifespan will increase modestly over the next decades. It almost certainly will, assuming continued success in reducing old-age morbidity and mortality1. Rather, the issue is whether postponing human ageing and natural death for many decades, possibly indefinitely, is feasible. Here, we discuss what we do and do not know about the mechanisms of ageing, and whether we have sufficient knowledge to foresee substantially retarding, halting or even reversing the degeneration and disease that limit human lifespan.
    Top of page
    Lifespan is plastic

    Ageing research has suffered more than disease-oriented research from unsubstantiated claims of potential cures. The field is also rife with opposing claims—that human life cannot be extended beyond a soft limit (120–125 years). For example, predictions in 1990 claimed that declines in death rates would not reach levels required for life expectancy at birth to exceed 85 years (ref. 2). However, Japanese females have already surpassed this limit (http://miranda.sourceoecd.org.ezproxy1.lib.asu.edu/vl=2231472/cl=20/nw=1/rpsv/health2007/
    g2-1-02.htm), and life expectancy in developed countries is now predicted to exceed 85 years by the year 2050 (ref. 1). A question remains as to whether science can free us from the bonds that seem to fix our lifespan.

    With the discovery in the 1980s that mutations in single genes can significantly extend lifespan in the nematode Caenorhabditis elegans3, 4, ageing began to be viewed as malleable by methods used to understand and manipulate development and disease. At present, hundreds of mutant genes can increase longevity in model organisms, including nematodes, yeast (Saccharomyces cerevisiae), fruitflies (Drosophila melanogaster) and mice (Mus musculus). Most act in evolutionarily conserved pathways that regulate growth, energy metabolism, nutrition sensing and/or reproduction5. Examples include genes encoding components of the insulin/insulin-like growth factor 1 (IGF-I) signalling (IIS) pathway, the target of rapamycin (TOR) pathway, and the mitochondrial electron transport chain (Fig. 1). In most cases, lifespan extension occurs when activity of the component is diminished. This abatement is thought to reduce somatic damage and/or increase somatic maintenance and repair5. Most pro-longevity mutations are discovered by mutagen or RNA interference screens, which mainly uncover inactivated or diminished gene functions, so further longevity mutations, resulting from enhanced gene function, may yet be discovered.
    Figure 1: Potentially conserved pro-ageing pathways, their interconnections and possible targets for intervention.
    Figure 1 : Potentially conserved pro-ageing pathways, their interconnections and possible targets for intervention. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

    In this very simplified depiction, three main pathways, the IIS, TOR and mitochondrial pathway, are indicated. The pro-ageing activities of these pathways are conserved across species, with energy sensors, such as AMPK, as potentially important hubs in the complex networks that integrate them. However, it is important to note potential dissimilarities among species as well. Most, if not all, defects in the mitochondrial respiratory chain are lethal or cause disease in humans62, but can increase lifespan in nematodes or yeast. In mammals, mitochondria play an important part in signalling apoptosis, which can either drive or retard ageing, depending on the cell type. There is evidence that many longevity signals converge on members of the FOXO and sirtuin protein families, which can interact. Note that SIR proteins can both activate and repress FOXO. Moreover, the effects of FOXO and SIR2 in cells can be either beneficial (for example, increasing antioxidant defence) or detrimental (for example, apoptosis), and may or may not promote organismal survival. For example, in mammals, SIRT1 dampens apoptosis by repressing FOXO, but also by repressing BAX activation, thereby preventing its oligomerization into the mitochondria outer membrane (cross), which normally triggers permeabilization of the membrane and release of soluble apoptogenic factors, such as cytochrome c, into the cytosol. Apoptosis can be beneficial, for example, by eliminating damaged cells and preventing cancer, or can be detrimental, by eliminating irreplaceable cells, such as neurons.
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    Many pro-longevity mutations mimic dietary restriction—underfeeding without malnutrition—which was shown to extend lifespan in laboratory rodents almost a century ago6. Dietary restriction increases longevity in many species, including yeast, nematodes, spiders and dogs. Although dietary restriction phenotypes often overlap with those conferred by dampening pro-ageing pathways, in some cases dietary restriction synergizes with pro-longevity mutations, indicating that dietary restriction can act independently7.

    The appreciation that lifespan is plastic and under negative influence by genes that favour growth or procreation fuels hopes of finding small molecules that target the pathways affected by dietary restriction or pro-longevity mutations8, 9. Compounds have been identified that show promise in this regard (Box 1), although none has yet shown major effects on lifespan in healthy mice10. Most, however, are in clinical trials to treat ageing-related diseases, such as diabetes and cancer, and already had the attention of the pharmaceutical industry. Of note, the US Food and Drug Administration will not approve agents that merely impede ageing. Nevertheless, it is remarkable that barely two decades ago human lifespan extension was a fantasy, whereas now pharmacological strategies are being considered for exactly that purpose. For some, the discovery that mutations in evolutionarily conserved pathways can greatly extend lifespan in model organisms is a step towards curing ageing in humans. As we argue, this viewpoint may be premature.
    Top of page
    Diminishing returns of complexity and idiosyncratic models

    There is ample evidence that much of basic biology is similar across species as divergent as yeast and humans11. This is also true for ageing. Studies of yeast, nematodes and flies undoubtedly illuminate our understanding of the evolutionary and mechanistic bases of human ageing. Still, the response of simple organisms to interventions might not be predictive when complexity increases, or when physiology deviates significantly from humans.

    The impact of complexity is illustrated by the IIS pathway. Invertebrates have a single receptor that binds ligands similar to insulin or IGF-1. Mutations that partially blunt signalling from this receptor extend lifespan in nematodes and flies5. However, mammals have distinct receptors for insulin and IGF-1, with different but overlapping functions. IGF-I primarily controls growth, whereas insulin regulates metabolism. In mammals, defective insulin signalling causes insulin resistance and diabetes. Defective IGF-I signalling causes protein breakdown and muscle degeneration. Indeed, IGF-I overexpression reduces ageing-associated cardiac dysfunction12 and improves muscle regeneration13. Nonetheless, reduced insulin signalling specifically in adipose tissue, or reduced IGF-I signalling throughout the animal, modestly extends lifespan in mice14, 15. So, tissue-specific modulation of particular signalling pathways might retard ageing in humans.

    The impact of complexity is also illustrated by interactions of two longevity-modulating protein families: forkhead (FOXO) transcription factors and silent information regulator (SIR) protein deacetylases (sirtuins). FOXO proteins (DAF-16 in nematodes) are required for the lifespan extension conferred by IIS mutations, and overexpression of SIR2 orthologues increases lifespan in yeast, nematodes and flies5. Mammals have multiple FOXO and SIR proteins. Some FOXO proteins initiate stress-induced cell death (apoptosis), which eliminates damaged or dysfunctional cells. FOXO proteins also upregulate antioxidant defence and DNA repair-facilitating genes16. FOXO is deacetylated by the human SIR2 orthologue SIRT1, which increases FOXO-dependent resistance to oxidative stress and cell-cycle arrest, but inhibits FOXO-dependent apoptosis17. SIRT1 also deacetylates the p53 tumour suppressor protein, attenuating its transcriptional activity and suppressing stress-induced apoptosis and cellular senescence (irreversible cell cycle arrest)18.

    A priori, it is difficult to predict whether increased FOXO or sirtuin activity should increase or decrease mammalian longevity. Mammals rely on apoptosis and senescence to suppress cancer19, which is a major age-related disease and challenge to the longevity of mammals. This is not the case for yeast, flies and nematodes, which do not or rarely develop cancer because they are unicellular or as adults they contain largely post-mitotic somatic cells.

    The magnitude of longevity extensions is worth noting. Genetic dampening of IIS routinely increases lifespan in nematodes twofold5, and one mutation increases lifespan tenfold20. In flies, however, single-gene mutations in the IIS or other pro-ageing pathways generally extend lifespan by only 25%–30%21. In mice, inactivating mutations in the Pou1f1, Prop1, or growth hormone receptor genes (which reduce IGF-I signals) increase lifespan by 40%22, whereas mutations that directly affect IIS extend lifespan by 20% or less14, 15.

    Thus, reduced IIS can substantially increase lifespan in nematodes, but much less so in the more complex fly and mouse. We know very little about mechanisms responsible for these species-specific differences. Within a species, genetic background, environment and sex differences matter. For example, lifespan extension in the IIS mutant fly chico depends on food concentration23. In transgenic flies overexpressing human superoxide dismutase in motor neurons, longevity benefits varied considerably among ten wild-derived genotypes, as well as by sex24.

    Although it is possible that we have not yet defined optimal conditions for downregulating conserved ageing pathways in organisms more complex than nematodes, other characteristics set nematodes apart. First, many of the initial longevity mutations identified in nematodes affect an alternative developmental stage termed dauer, which suspends reproduction and alters metabolism. Hibernation, which temporarily suspends mammalian metabolism and reproduction, never lasts longer than the lifespan, in contrast to the dauer state in nematodes. Second, aerobic respiration is less critical for nematodes than for flies and mammals. This may explain why RNA interference screens for increased lifespan in nematodes identified multiple genes encoding mitochondrial respiratory chain subunits25. Downregulating these genes may increase lifespan by reducing mitochondrial function and its toxic by-products. In mammals, similar downregulation might be lethal or cause serious disease.
    Top of page
    Translation to humans

    Although disrupting conserved pro-ageing pathways identified in model organisms seems a realistic starting point for human lifespan extension, we first must determine whether these pathways modulate ageing in our own species. An initial approach is to identify associations between polymorphisms in or around conserved genes and human longevity. Extreme human longevity is genetically controlled, as indicated by the higher chance of siblings of centenarians to survive more than 100 years and moderate familial clustering of extreme longevity26. Thus far, however, linkage analyses are inconclusive, possibly because studies were underpowered or because of admixture in control populations27.

    Attempts to associate candidate genes with extreme human longevity have mainly identified variants in lipoprotein metabolism genes as overrepresented in centenarians28. Furthermore, variants in FOXO1 and FOXO3 genes segregated with survival to age 85 and older29, and, in females, gene variants that reduce insulin/IGF-I signalling are associated with long survival30. Recently, heterozygous mutations in the IGF-IR, which markedly reduced IGF-IR activity, were found overrepresented in centenarians31.

    Although these results are promising, more research is needed to confirm that humans and model organisms use similar longevity-modulating pathways. Even if these pathways are conserved in Homo sapiens, their natural variation evidently does not extend lifespan as much as laboratory-generated mutations in model organisms, notably nematodes. It is possible that organismal complexity will limit how much lifespan extension can be achieved by manipulating metabolic pathways; or there could be other layers of control or pathways that are yet to be discovered in complex animals. In predicting lifespan extension in humans, it is important to remember that these are crucial questions and their answers are unknown.

    Life extension in model organisms may be an artefact to some extent. None of the laboratory animals considered ‘wild type’ has the genetic diversity of true wild strains, nor is the laboratory a natural habitat. For example, dietary restriction does not substantially increase longevity in some wild mice. Thus, laboratory breeding might select for a robust dietary restriction response32. Two longitudinal dietary restriction studies in rhesus monkeys were initiated in the late 1980s. Interim results suggest that dietary restriction improves health (for example, less body fat, higher insulin sensitivity and favourable circulating lipids), but there is no evidence yet that dietary restriction increases lifespan to the extent that it does in laboratory rodents33, 34. Moreover, in monkeys (and by extension, humans) some benefits of dietary restriction, such as low IGF-I levels, may decrease cancer risk, but also increase the risk of osteoporotic fractures35. Thus, it might be necessary to reduce IGF-I signalling during early adulthood to prevent cancer, but increase it at older ages to prevent non-cancerous diseases36.

    Can we expect interventions that target the human IIS pathway, even with proper spatio-temporal regulation, to extend lifespan to the extent that they do in simple models? Among the pro-longevity effects of dampening IGF-I signalling is upregulated stress resistance. Notably, stress response is generally superior in cells from long-lived compared to short-lived species37. In short-lived species, there is evidently sufficient opportunity for enhancing protective mechanisms. However, in long-lived species, there may be fewer such opportunities38.

    Furthermore, human physiology obviously differs from that of yeast, nematodes or flies. Perhaps less obvious are the differences between humans and mice. We should keep in mind that many anti-cancer therapies are successful in mice but fail in humans. Moreover, side or off-target effects of drugs that affect complex physiological pathways are already a problem. For example, cholesteryl ester transfer protein inhibitors, developed to increase high-density lipoprotein cholesterol, did not decrease but increased the risk of heart disease39.

    Before we can rationally evaluate the potential impact of interventions to increase human lifespan substantially, we will need to understand the primary causes of ageing, which leads to the important question of why and how we age.
    Top of page
    Evolutionary logic of ageing

    According to Dobzhansky40, “nothing in biology makes sense except in the light of evolution”; so it is in the biology of ageing. Most scientists now accept that ageing results from the greater weight placed by natural selection on early survival and reproduction than on vigour at later ages. This age-related decline in the force of natural selection, first articulated by Medawar41, is due to high mortality caused by extrinsic hazards in natural environments, resulting in a relative scarcity of older individuals. When these hazards make survival to old age rare, natural selection favours gene variants that promote early growth and reproduction. In less hazardous environments, survival increases and gene variants that promote somatic maintenance can propagate. Hence, species-specific lifespan is determined by a trade-off between somatic maintenance and early growth or reproduction (Fig. 2)42. For example, genes that ensure a powerful immune response to infection promote early life survival, but later contribute to inflammation, a major age-related phenotype and risk for developing many diseases43.
    Figure 2: Balancing somatic maintenance with growth and reproduction may determine lifespan.
    Figure 2 : Balancing somatic maintenance with growth and reproduction may determine lifespan. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

    According to the ‘disposable soma theory’63, organisms must compromise between energy allocation to growth and reproduction or somatic maintenance and repair.
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    Obviously, huge differences in longevity can arise as a result of evolution—consider the longevity difference between nematodes (weeks) and mammals (years), or even between mice (approx3 yr) and humans (approx100 yr). Were these differences achieved evolutionarily by discarding pro-ageing pathways, or by creating new longevity assurance pathways? The notable conservation among known longevity-modulating pathways, and similarities between organisms such as mice and humans in genomic structure and organization, argue against this possibility. Of course, unique non-conserved pathways may yet be discovered. It is more probable that significant longevity was achieved by subtle changes in many genes over the course of evolution, not by single mutations with large effects, which often increase lifespan at a cost to reproduction or survival under stress45. If so, interventions that target a single mammalian gene or even a single pathway may not increase longevity to the extent achieved by natural selection. This should not discourage the search for pharmacological interventions, but rather underscores how the shallowness of our knowledge about comparative evolutionary mechanisms can severely hamper efforts in this area.

    Despite a general consensus regarding the evolutionary basis of why we age, we still know little about the primary causes of ageing and its relation to disease, which is generally the cause of death.
    Top of page
    The ageing phenotype and the relationship to disease

    Emphasis on lifespan can distract from understanding ageing itself. In nematodes and flies, we know much about genes that determine lifespan, but little about how these animals die. This is due to the complexity of ageing phenotypes42 and our limited ability to define phenotype, in contrast to the relative ease of defining genotype.

    Table 1 lists some of the best-known ageing phenotypes in humans, which are increasingly evident in laboratory models as they are scrutinized. There are remarkable similarities among species, but there are also marked differences. For example, amyloid plaques in the brain and atherosclerotic plaques in blood vessels are hallmarks of human ageing, but are virtually lacking in mice. Even examination of shared phenotypes can uncover differences. For example, kyphosis (spinal curvature) is caused by osteoporosis in humans, but can have other causes, such as growth plate abnormalities, in mice. Importantly, ageing phenotypes—from hair greying to cancer susceptibility—vary among individual humans, and among inbred mouse strains.
    Table 1: Conserved ageing phenotypes
    Table 1 – Conserved ageing phenotypes

    Full table

    A prominent age-related phenotype in humans and mice, absent in nematodes and flies, is cancer. Cancer arises from renewable somatic tissues, which are largely lacking in invertebrates. Cancer is sometimes considered as the opposite of ageing because it entails more vigorous growth. Indeed, cellular senescence, the irreversible cessation of growth, was once considered a model for ageing in vivo, but is now known to be a stress and tumour suppressive response19. Senescent cells increase with age in mice, non-human primates and humans, but comprise only a fraction of cells in renewable tissues19. Cellular senescence may be another evolutionary trade-off, as it suppresses cancer at early ages, but may promote ageing by exhausting stem cells or altering their niches. Senescent cells secrete inflammatory cytokines and other molecules that alter tissue microenvironments, and could stimulate the growth of cells that harbour preneoplastic mutations46. On the other hand, increased cellular senescence (and decreased proliferative potential) could also explain the decrease in cancer incidence rate at very old age, that is, after age 80 (ref. 47). Hence, cellular senescence can act both as a carcinogen and as an anti-carcinogen.

    Little is known about ageing phenotypes and the causes of death in C. elegans. The nervous system is remarkably preserved, but ageing nematodes show slower movement, lower pharyngeal pumping rates (due to muscle deterioration resembling human sarcopenia) and increased lipofuscin48. Notably, there is extensive variability in age-related degeneration among genetically identical animals and cells of the same type within an individual48. This finding emphasizes the potentially important role of stochastic events in ageing, a point to which we will return.

    Also in Drosophila, little is known about ageing or the causes of death. Nonetheless, this organism is emerging as a powerful model for human age-related diseases, such as Parkinson’s disease49. Ageing flies also develop sarcopenia and accumulate lipofuscin, so these traits may be universal ageing phenotypes50. Flies also show signs of cognitive dysfunction (increased time to accomplish a task), sharing this phenotype with mice and humans (Table 1).

    Should we distinguish between ageing and disease? The answer to this question, which is still debated, depends on the disease and how its mechanism relates to ‘intrinsic ageing’; that is, ageing-related changes that are not determined primarily by external factors or genetic predisposition. Early-onset diseases, such as sickle cell anaemia, caused by a heritable beta-globin gene mutation, can result at young ages in vascular constriction and increased risk of infection, also common in older people. But because these phenotypes occur within the realm of natural selection, sickle cell anaemia is not an ageing-related disease as its causes have little to do with ageing. Such a mechanistic distinction is much more difficult for late-onset diseases. Many would distinguish potentially fatal vascular degeneration from benign greying of hair. However, both phenotypes could have the same cause: intrinsic ageing. On the other hand, different mechanisms might produce the same disease-related phenotype at old age. For example, intrinsic endothelial cell ageing might contribute to atherosclerosis, as do mutations or polymorphisms in genes encoding the low-density lipoprotein receptor or ApoB. Statins can lower cholesterol and suppress atherosclerosis in individuals with high-risk low-density lipoprotein receptor or ApoB alleles, but cannot prevent intrinsic endothelial cell ageing.

    Diseases are the main causes of death in elderly humans. Arteriosclerosis, diabetes, dementia, osteoporosis, osteoarthritis and cancer are particularly prominent pathologies, and some account for much of mortality at old age. Among the old who escape these diseases, the cause of death is often unknown. However, because interactions among ageing phenotypes are complex, natural death may ultimately be traced to disease, even if occult. For example, subtle tissue atrophies, neuropathies or microvascular leakage may underlie the deaths of old people subjected to stress. It is not clear whether successful intervention in overt disease will ameliorate intrinsic ageing, and thus significantly extend human lifespan.

    Ageing is influenced by genetic and environmental factors that may be unrelated to each other or to intrinsic ageing. Irrespective of possible intrinsic ageing mechanisms, alleles that promote ageing will penetrate the germ line as long as their adverse effects manifest late enough, creating a diversity of genetic risk factors. Even among inbred individuals, for example, monozygotic human twins, genetic diversity occurs in somatic cells by mutation and epimutation at very early ages51, 52. Similarly, environmental or lifestyle factors (for example, sunlight or smoking) can accelerate intrinsic ageing in specific tissues. It is conceivable that individuals of extreme longevity (that is, 100 years and older) are primarily those who managed to escape these genetic and environmental risks. This possibility is supported by the decelerated mortality rate seen at old age in invertebrate and human populations, indicating the survival of increasingly less frail individuals53. A question remains as to whether these survivors that escape the genetic and environmental risks that normally eliminate individuals through disease succumb to intrinsic ageing. Is there really an intrinsic ageing mechanism(s) to which eventually every cell or tissue falls prey? If so, what is its basis?
    Top of page
    Intrinsic ageing

    Ageing entails numerous functional and structural changes, many, but not all of which, adversely affect survival. A universal process of ‘intrinsic ageing’ might explain common ageing phenotypes among animals. One characteristic shared by all species studied thus far is the accumulation of unrepaired somatic damage. Thus, lifelong accumulation of various types of damage, along with random errors in bioinformational processes, might underlie intrinsic ageing (Fig. 3). As discussed, attenuation of such damage could explain the longevity conferred by mutations that dampen normal metabolic processes. Moreover, defence systems that keep damage in check might differ in efficacy among species, thereby dictating their lifespan37.
    Figure 3: The causes of intrinsic ageing.
    Figure 3 : The causes of intrinsic ageing. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

    Although ultimately stochastic in nature, the proximal causes of ageing involve both programmed and random mechanisms.
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    Prominent causes of somatic damage include reactive oxygen species (ROS) and reducing sugars. ROS (by-products of respiration and other metabolic processes54) can damage and crosslink DNA, proteins and lipids. Reducing sugars react with carbohydrates and free amino groups, resulting in difficult-to-degrade advanced glycation end products (AGEs)55. AGEs accumulate in long-lived structural proteins, such as collagen and elastin. They increase the stiffness of blood vessels, joints and the bladder, and impair function in the kidney, heart, retina and other organs.

    Interventions that remove damage might successfully counter the adverse effects of ROS and AGEs, thereby postponing ageing indefinitely56 (see Box 1). However, macromolecular damage comes in many forms and all key lesions may not have been identified. Moreover, we do not know their relative contributions to intrinsic ageing, or how various components of the damage spectrum interact.

    It might seem more efficacious to eliminate damaging molecules, rather than damage itself. However, some damaging molecules are crucial for normal cellular function. Two examples are glucose, which clearly cannot be eliminated, and ROS, which are also signalling molecules57. Trade-offs between beneficial and deleterious effects of damaging molecules will complicate strategies aimed at extending longevity by neutralizing them.

    A similar trade-off might be cellular processes that defend us against cancer. Tissue regeneration elevates cancer risk by increasing the chance of acquiring DNA mutations or epimutations, which occur frequently in every organism as a consequence of errors during the repair or replication of a damaged template. Tumour suppressor mechanisms either eliminate cells that acquired extensive damage (apoptosis) or permanently prevent their proliferation (senescence). These responses, however, may gradually cause tissue atrophy, and therefore loss of organ function and regenerative capacity (Fig. 3)58. In principle, stem cell transplantation could counter the adverse effects of these damage responses.

    When damage levels are not high enough to elicit an apoptotic or senescence response, a potentially more serious situation ensues that is difficult to counter: the gradual accumulation of random changes in DNA or protein, turning tissues into cellular mosaics. Such stochastic changes can reset gene regulatory loops, and randomly alter gene expression patterns on a cell by cell basis59, 60. These changes, in aggregate, might compromise tissue function, without eliciting immediate cellular responses (Fig. 3). Stochastic gene regulatory drift would be difficult to correct and could even occur in stem cells in vivo or ex vivo during expansion for transplantation therapy.

    Furthermore, developmental pathways that are essential for early life fitness or reproduction might be deleterious in adult tissues—for example, pathways that drive ductal morphogenesis in the developing or pregnant mammary gland might gradually promote ductal hyperplasia in the adult gland, predisposing it to cancer.
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    Future prospects

    There is abundant evidence for mortality decline and increased lifespan throughout the developed world1. Before 1970, this probably reflected improvements in the food supply and sanitation, and achievements in medicine, notably vaccination and antibiotics. After 1970, the mortality decline probably reflects preventive medicine, lifestyle changes, routine use of anti-hypertensive and other drugs, and so on. It is impossible to predict, at this stage, whether increasingly sophisticated interventions will negate most or all ageing phenotypes. However, there are reasons for caution.

    First, pharmacological intervention on the basis of pathways identified in model organisms may be an illusion because gains in longevity achieved in these organisms seem to decline with organismal complexity or depend on idiosyncratic physiology. Furthermore, lifespan in some organisms may be less plastic than in others. In addition, cancer poses a challenge to longevity that is distinct from age-related degeneration, and may be suppressed by mechanisms that are also pro-ageing. Third, there are still enormous gaps in our knowledge about how metabolic pathways operate and interact; serious side effects may constrain the effectiveness of pharmacological interventions.

    Repair of macromolecular damage may prove more promising, especially in unison with improved anti-cancer therapies. However, it is not clear that all toxic lesions have been identified, or whether practical strategies exist to eliminate them. For example, it would be impossible to counter (epi)genomic drift pharmacologically, and transplanted organs and cells are also subject to loss of (epi)genomic integrity. Moreover, we do not know if macromolecular damage is the sole cause of ageing. Even in simple organisms, it is clear that longevity-modulating pathways entail exquisitely balanced interactions, regulated by numerous genetic elements61. And the large number of genomic transactions makes errors—many that are irreversible—inevitable. Indeed, there is evidence that ageing entails a gradual drift towards more random patterns of gene expression59, which might cause organ/tissue failure that cannot be undone by pharmacological or biological intervention.

    In theory, interventions could be designed to alter the orchestrated networks of cell–cell interaction to increase lifespan. This is essentially what evolution has done to produce long-lived species. The question is, can we mimic the evolutionary process to the extent that senescence becomes essentially negligible? At this stage, the answer must be that we do not know. Although there is no scientific reason for not striving to cure ageing—similar to what we profess to do for cancer and other diseases—our current understanding makes it impossible to assert that indefinite postponement is feasible. Rather, we need to use the current momentum to intensify research aimed at resolving major outstanding questions that hinder a more complete understanding of basic ageing mechanisms and their relationship to disease (Box 2). Only this will allow us to generate sophisticated, integrated strategies to increase human health and lifespan.

    • Other Night Cat permalink
      August 22, 2009 1:57 PM

      “Let’s assume – dear, animate reader – that you and me and we want to live. What can we do? I encourage you to think about this.”

      Oh, the hard question again. I would like a lifetime or 2 of quiet time off to think about that, please… Hah, let’s leave it to others, is that the answer? Rally, organize, empower those who think they may have a piece of the puzzle. I do not see a more direct way to truly help.

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