Is aging programed?

Development and morphogenesis may easily be thought of as programed, in the sense that they result from a sequence of cellular and molecular events designed by natural selection to produce a given adult phenotype. Aging, except in exceptional cases such as the rapid decay and death of Pacific salmon, is not design but decay. The decay of senescence is not due to natural selection's designing hand, but to its absence. The empirical difference between programed and nonprogramed senescence becomes evident when comparing the stereotypical steps leading to death in salmon contrasted with the lack of such stereotypy in most organisms such as humans and mice. Understanding the distinction between programed development and nonprogramed senescence helps focus attention on the phenotypic performance of adults, which is the focus of natural selection, and therefore be attentive to any unwanted pleiotropic side-effects of genetic or environmental treatments which retard aging.     

Update on the oxidative stress theory of aging: Does oxidative stress play a role in aging or healthy aging?

The oxidative stress theory of aging predicts that manipulations that alter oxidative stress/damage will alter aging. The gold standard for determining whether aging is altered is life span, i.e., does altering oxidative stress/damage change life span? Mice with genetic manipulations in their antioxidant defense system designed to directly address this prediction have, with few exceptions, shown no change in life span. However, when these transgenic/knockout mice are tested using models that develop various types of age-related pathology, they show alterations in progression and/or severity of pathology as predicted by the oxidative stress theory: increased oxidative stress accelerates pathology and reduced oxidative stress retards pathology. These contradictory observations might mean that (a) oxidative stress plays a very limited, if any, role in aging but a major role in health span and/or (b) the role that oxidative stress plays in aging depends on environment. In environments with minimal stress, as expected under optimal husbandry, oxidative damage plays little role in aging. However, under chronic stress, including pathological phenotypes that diminish optimal health, oxidative stress/damage plays a major role in aging. Under these conditions, enhanced antioxidant defenses exert an “antiaging” action, leading to changes in life span, age-related pathology, and physiological function as predicted by the oxidative stress theory of aging.     

Does p53 affect organismal aging?

The p53 protein plays a critical role in the prevention of cancer. It responds to a variety of cellular stresses to induce either apoptosis, a transient cell cycle arrest, or a terminal cell cycle arrest called senescence. Senescence in cultured cells is associated with augmented p53 activity and abrogation of p53 activity may delay in vitro senescence. Increasing evidence suggests that p53 may also influence aspects of organismal aging. Several mutant mouse models that display alterations in longevity and aging-related phenotypes have defects in genes that alter p53 signaling. Recently, my laboratory has developed and characterized a p53 mutant mouse line that appears to have an enhanced p53 response. These p53 mutants exhibit increased cancer resistance, yet have a shortened longevity and display a number of early aging-associated phenotypes, suggesting a role for p53 in the aging process. The nature of the aging phenotypes observed in this p53 mutant line is consistent with a model in which aging is driven in part by a gradual depletion of stem cell functional capacity.     

Does premature aging of the mtDNA mutator mouse prove that mtDNA mutations are involved in natural aging?

Recent studies have demonstrated that transgenic mice with an increased rate of somatic point mutations in mitochondrial DNA (mtDNA mutator mice) display a premature aging phenotype reminiscent of human aging. These results are widely interpreted as implying that mtDNA mutations may be a central mechanism in mammalian aging. However, the levels of mutations in the mutator mice typically are more than an order of magnitude higher than typical levels in aged humans. Furthermore, most of the aging-like features are not specific to the mtDNA mutator mice, but are shared with several other premature aging mouse models, where no mtDNA mutations are involved. We conclude that, although mtDNA mutator mouse is a very useful model for studies of phenotypes associated with mtDNA mutations, the aging-like phenotypes of the mouse do not imply that mtDNA mutations are necessarily involved in natural mammalian aging. On the other hand, the fact that point mutations in aged human tissues are much less abundant than those causing premature aging in mutator mice does not mean that mtDNA mutations are not involved in human aging. Thus, mtDNA mutations may indeed be relevant to human aging, but they probably differ by origin, type, distribution, and spectra of affected tissues from those observed in mutator mice.     

Is coarse-to-fine strategy sensitive to normal aging?

Theories on visual perception agree that visual recognition begins with global analysis and ends with detailed analysis. Different results from neurophysiological, computational, and behavioral studies all indicate that the totality of visual information is not immediately conveyed, but that information analysis follows a predominantly coarse-to-fine processing sequence (low spatial frequencies are extracted first, followed by high spatial frequencies). We tested whether such processing continues to occur in normally aging subjects. Young and aged participants performed a categorization task (indoor vs. outdoor scenes), using dynamic natural scene stimuli, in which they resorted to either a coarse-to-fine (CtF) sequence or a reverse fine-to-coarse sequence (FtC). The results show that young participants categorized CtF sequences more quickly than FtC sequences. However, sequence processing interacts with semantic category only for aged participants. The present data support the notion that CtF categorization is effective even in aged participants, but is constrained by the spatial features of the scenes, thus highlighting new perspectives in visual models.     

Impaired mitophagosome–lysosome fusion mediates olanzapine-induced aging

The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome–lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome–lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.     

Peroxisome proliferator-activated receptor-γ protects against vascular aging

Vascular disease occurs commonly during aging. Carotid artery and cerebrovascular disease are major causes of stroke and contributors to dementia. Recent evidence suggests that peroxisome proliferator-activated receptor-γ (PPARγ) may play a protective role in the vasculature, but the potential importance of PPARγ in vascular aging is unknown. To examine the hypothesis that PPARγ normally protects against vascular aging, we studied heterozygous knockin mice expressing a human dominant-negative mutation in PPARγ (P465L, designated L/+). Endothelial dysfunction, a major contributor to vascular disease, was studied using carotid arteries from adult (8 ± 1 mo) and old (24 ± 1 mo) L/+ mice and wild-type littermates. In arteries from wild-type mice, responses to the endothelium-dependent agonist ACh were similar in adult and old wild-type mice but were reduced by ～50% in old L/+ mice (n = 7-10, P < 0.05). Impaired responses in arteries from old L/+ mice were restored to normal by a scavenger of superoxide. Relaxation of arteries to nitroprusside (an NO donor) was similar in all groups. Contraction of arteries to U46619 was not affected by age or genotype, while maximal responses to endothelin-1 were reduced with age in both wild-type and L/+ mice. Vascular expression (mRNA) of the catalytic component of NADPH oxidase (Nox2) was not altered in wild-type mice but was increased significantly in old L/+ mice. These findings provide the first evidence that interference with PPARγ function accelerates vascular aging, suggesting a novel role for PPARγ in protecting against age-induced oxidative stress and endothelial dysfunction.     

New data on programmed aging — slow phenoptosis

This review summarizes the latest data on biochemistry and physiology of living organisms. These data suggest that aging, i.e. coordinated age-dependent weakening of many vital functions leading to gradual increase in the probability of dying, is not common to all organisms. Some species have been described whose probability of death does not depend on age or even decreases with age, this being accompanied by constant or increasing fertility. In the case of the naked mole rat (a non-aging mammal), a mechanism has been identified that protects this animal from cancer and the most common age-related diseases. The high molecular weight polysaccharide hyaluronan, a linear polymer composed of multiple repeated disaccharide of glucuronic acid and glucosamine, plays the key role in this mechanism. Hyaluronan is accumulated in the intercellular spaces in the organs and tissues of the naked mole rat. This polysaccharide provides early contact inhibition of cell division (anti-cancer effect). In addition, hyaluronan prevents the development of certain types of apoptosis, in particular, those induced by reactive oxygen species (ROS) (geroprotective effect preventing ROS-induced decrease in cellularity in the organs and tissues of aging organisms). Extraordinary longevity of the naked mole rat (over 30 years, which is long for a rodent the size of a mouse) is connected to its eusocial lifestyle, when only the “queen” and its few “husbands” breed, while the huge army of non-breeding “subordinates” provide the “royal family” with protection from predators, food, and construction and maintenance of an underground labyrinth size of a football field. This way of life removes the pressure of natural selection from the “family” and makes aging — the program that is counterproductive for the individual but increases “evolvability” of its offspring — unnecessary. The example of the naked mole rat demonstrates the optional character of the aging program for the organism. Many facts indicating that aging can be regulated by an organism provide another argument in favor of optionality of aging. Cases have been described when aging as a program useful for the evolution of offspring but counterproductive for the parental individual slows under conditions that threaten the very existence of the individual. These conditions include food restriction (the threat of death from starvation), heavy muscular work, decrease or increase in the environmental temperature, small amounts of poisons (including ROS; here we speak about the paradoxical geroprotective effect of the low doses of prooxidants that inhibit apoptosis). On the other hand, aging can be inhibited (and maybe even cancelled) artificially. This can be done by turning off the genes encoding the proteins participating in the aging program, such as FAT10, p66shc, and some others. In addition, the gene of the antioxidant enzyme catalase can be addressed into mitochondria, where it will split mitochondrial hydrogen peroxide, the level of which increases with age. However, today the simplest way to slow down the aging program is the use of mitochondria-targeted low molecular weight antioxidant compounds of plastoquinonyl decyltriphenylphosphonium-type (SkQ1), which prolong the life of animals, plants, and fungi and inhibit the development of many age-related diseases and symptoms.     

Can aging be programmed? A critical literature review

The evolution of the aging process has long been a biological riddle, because it is difficult to explain the evolution of a trait that has apparently no benefit to the individual. Over 60 years ago, Medawar realized that the force of natural selection declines with chronological age because of unavoidable environmental risks. This forms the basis of the mainstream view that aging arises as a consequence of a declining selection pressure to maintain the physiological functioning of living beings forever. Over recent years, however, a number of articles have appeared that nevertheless propose the existence of specific aging genes; that is, that the aging process is genetically programmed. If this view were correct, it would have serious implications for experiments to understand and postpone aging. Therefore, we studied in detail various specific proposals why aging should be programmed. We find that not a single one withstands close scrutiny of its assumptions or simulation results. Nonprogrammed aging theories based on the insight of Medawar (as further developed by Hamilton and Charlesworth) are still the best explanation for the evolution of the aging process. We hope that this analysis helps to clarify the problems associated with the idea of programmed aging.     

Which aging in yeast is “true”?

Two model systems, “replicative aging” and “chronological aging” (CA), which are used for gerontological research on the yeast Saccharomyces cerevisiae, are compared. In the first case, the number of daughter cells generated by an individual mother cell before cell propagation irreversibly stops is analyzed. This makes the model very similar to the well-known Hayflick model. In the case of CA, the survival of yeast cell population in the stationary phase of growth is studied. It is noted that the second model is similar to the “stationary phase aging” model, which is used in the author’s laboratory for cytogerontological studies on animal and human cells. It is assumed that the concept of cell proliferation restriction as the main cause of age-related accumulation in the cells of multicellular organisms of macromolecular defects (primarily DNA damage) leading to deterioration of tissue and organ functioning and, as a result, to an increase in the death probability allows explaining how the aging process proceeds in almost any living organisms. Apparently, in all cases, this process is initiated by the appearance of slow propagating (or not propagating at all) cells, which leads to the termination of “dilution,” with the help of new cells, of macromolecular defects accumulating at the level of whole cell population. It is concluded that data on the geropromoter or geroprotector activity of various factors obtained in tests on the yeast CA model can be used with a high reliability to understand the mechanisms of human aging and longevity.     

Will the real aging Sirtuin please stand up?

Initial studies linking Sirtuins to longevity in yeast initiated what is now a rich vein of aging research that is full of promise and fraught with controversy. Missing was a demonstration that enhanced Sirtuin expression extends lifespan in mammals. Now Kanfi et al. provide the evidence but with an interesting plot twist – the lesser known SIRT6 is the longevity factor.While Sirtuins, a highly conserved class of protein deacetylases, have been linked to longevity in a variety of model organisms and are among the most studied proteins in the context of aging, their role remains controversial. Increased expression of the founding member of the class, yeast SIR2, was reported to extend replicative lifespan over a decade ago and this was followed by reports that overexpression of SIR2 orthologs leads to enhanced longevity in worms and flies ^{1, 2}. More recent reports have called the worm and fly data into question ^{3, 4} and while increased Sir2 activity may enhance longevity under certain conditions in all three organisms, mechanistic studies have not converged on a specific activity coupled to aging.Seven mammalian Sir2 homologs (SIRT1-SIRT7) have been identified. A myriad of activities in a range of mammalian tissues have been attributed to SIRT1, a protein most structurally related to yeast Sir2, often linked to protection from the onset of chronic disease states. Yet transgenic mice with increased SIRT1 expression are not long-lived ⁵, further adding to what is becoming a great science mystery. Until recently, while SIRT1 was being intensely studied, the other Sirtuins were mostly waiting in the wings. In the last few years, however, many of them have been linked to interesting biological functions and, with the recent report by Kanfi et al. ⁶, SIRT6 assumes a central role in aging.The primary finding of Kanfi et al. is that transgenic mice overexpressing SIRT6 have enhanced longevity, but only in males ⁶. While the longevity enhancement is modest (15% increase in median lifespan), the data is rigorous. Similar effects were seen in two different founder transgenic lines, large numbers of mice were included in the study and a mixed genetic background was selected for the study with equal contribution of two long-lived inbred backgrounds. The authors also attempted to address whether the longevity benefit results from retarded aging, as opposed to protection from cancer, a common cause of mortality in mice. While a challenging issue to resolve in a single study, tantalizing evidence is provided that SIRT6 is indeed a modulator of aging. For instance, if longevity is enhanced simply by eliminating the most common type of cancer, lung in these mice, then a post-mortem analysis would yield a skewing of the tumor spectrum. Yet no significant differences were seen in the incidence of different tumors. Moreover, other age-related pathologies were evident in equal proportion. These findings are consistent with a model whereby the aging process is delayed, with animals developing and succumbing to the same diseases later in life (Figure 1). Coupled with earlier findings that SIRT6 overexpression in mice (1) leads to protection from diet-induced obesity and (2) suppresses expression of NF-κB-dependent inflammatory markers, and moreover that SIRT6 expression is induced by caloric restriction in rats, it is fair to say that the deacetylase has certainly entered the realm of top-tier candidate modulatory factors of aging.Open in a separate windowFigure 1SIRT6 expression and longevity. Decreased SIRT6 expression leads to genome instability, as well as progeroid phenotypes that resemble accelerated aging. In contrast, increased SIRT6 expression alters cell and physiological phenotypes in a manner that promotes enhanced longevity.Long debated is whether mouse or human models of progeria, diseases with a rapid onset of a subset of aging pathologies, are truly accelerated aging syndromes ⁷. One argument against this hypothesis was that the genetic interventions giving rise to progeroid syndromes are non-overlapping with those linked to enhanced longevity. This disconnect is starting to dissolve as genes that go both ways are being identified. p53 is arguably the first example; constitutive p53 activation induces progeria phenotypes ⁸, whereas enhanced p53 activity under normal regulatory control leads to lifespan extension ⁹. With the study by Kanfi et al. ⁶, SIRT6 emerges as a new member of this short list of genes since it was previously shown that SIRT6^−/− mice have metabolic defects and rapidly present with abnormalities often associated with aging, such as kyphosis and loss of subcutaneous fat ¹⁰. Thus, reduced SIRT6 expression may accelerate aspects of aging whereas enhanced SIRT6 expression may delay them.A primary question is why increased SIRT6 expression enhances longevity, and several models are possible in addition to regulation of NF-κB. First are the metabolic consequences of enhanced SIRT6 activity, which are further elaborated in Kanfi et al. by examination of metabolic changes during aging of mice on a normal ad lib diet ⁶. First, Sirt6-transgenic mice are able to maintain healthy glucose metabolism later in life than controls, a feature often associated with longevity. However, both males and females maintain better metabolic function, therefore, this finding, while it may be linked, is separable from the dimorphic effects on lifespan. A further clue comes from the finding that IGF-1 levels are reduced in serum of male but not female overexpressing SIRT6 and that this is coupled to a corresponding increase in IGFBP-1 levels. Interestingly, these changes place the males in line with the females with regard to both factors. The downstream consequences of reduced IGF-1 levels are most apparent in white adipose tissue, which show significant reductions in AKT phosphorylation again only in males. Metabolic changes in fat tissue are increasingly linked to lifespan. These findings raise the intriguing possibility that the enhanced longevity in male Sirt6-transgenic mice occur because they have metabolic profiles more like that of females.Whole-genome microarray analysis of liver tissue from mice overexpressing SIRT6 raises another intriguing possible mechanism linked to metabolism. First, the biggest gene expression changes were apparent in male transgenic livers and, importantly, many of the observed differences overlap with those of calorie-restricted mice. Since those mice also have reduced serum IGF-1 and increased IGFBP-1 levels ¹¹, gene expression changes could be cause or consequence of changes to the endocrine axis. Moreover, these findings support the hypothesis that SIRT6 overexpression phenocopies aspects of calorie restriction in males. Another possibility that Sirt6-transgenic mice eat less, mimicking calorie restriction in a more direct fashion, can be largely discounted since an early study reported equal food consumption ¹².While SIRT1 is relatively promiscuous in its choice of substrate for deacetylation, finding targets for SIRT6 proved a more challenging endeavor. Recently, however, the identification of histone H3K9 and K56 may explain roles identified for SIRT6 in the DNA damage response and in telomere maintenance ^{13, 14}. Cells from SIRT6^−/− mice experience a dramatic elevation in genome instability indicative of defective double strand break (DSB) repair ¹⁰ and by contrast, enhanced SIRT6 activity stimulates DSB repair, particularly in response to oxidative stress ¹⁵. Deacetylation of H3K56 is linked to enhanced DNA repair, as is mono-ADP ribosylation of PARP, an alternate NAD⁺-dependent enzymatic activity of SIRT6. SIRT6 also associates with telomere heterochromatin, where it deacetylates both H3K9 and H3K56 ^{13, 16}. Reduced SIRT6 expression in primary fibroblasts leads to a range of replication-dependent defects in telomere maintenance, promoting premature senescence. Functions of SIRT6 either at sites of DSBs or at telomeres could underlie both progeroid and/or enhanced longevity phenotypes.While SIRT1 resembles yeast Sir2 from a structural perspective, it may be SIRT6 that is a closer functional ortholog. In their respective organisms, expression levels of each correlate with longevity. Moreover, both are most closely linked with histone deacetylation and have roles in genome maintenance both at telomeres and in response to DNA damage. Both also may link genome maintenance to nutrient and stress conditions in the cell. A challenge moving ahead will be to link SIRT6 enzymatic functions and cellular properties to the metabolic and longevity phenotypes apparent in the transgenic and knockout mice.The studies of Kanfi et al. place SIRT6 in a group of genes that when genetically modified can lead to enhanced mammalian longevity. However, they do not rule out roles for other Sirtuins in aging. For instance, while whole body overexpression of SIRT1 appears not to enhance lifespan, given the range of its functions in different tissues, more informative may be the lifespan phenotypes of mice overexpressing SIRT1 in specific tissues. In addition, little is known about other Sirtuins and given interesting metabolic roles especially for those localized to the mitochondria, it would not be surprising if they affect aging as well ². The role of Sirtuins in aging remains controversial and undoubtedly twists and turns are yet to come, but the report by Kanfi et al. makes the case for Sirtuins and aging far more compelling, at least in the case of SIRT6.     

Short telomeres: cause or consequence of aging?

Questions about mechanisms, about the direction of causality, and about cellular heterogeneity complicate interpretation of claims associating short telomeres with adverse health outcomes.     

Why is oocyte aneuploidy increased with maternal aging?

One of the main causes of pregnancy failure and fetus abortion is oocyte aneuploidy, which is increased with maternal aging. Numerous possible causes of oocyte aneuploidy in aged women have been proposed, including cross-over formation defect, cohesin loss, spindle deformation, spindle assembly checkpoint malfunction, microtubule-kinetochore attachment failure, kinetochore mis-orientation, mitochondria dysfunction-induced increases in reactive oxygen species, protein over-acetylation, and DNA damage. However, it still needs to be answered if these aneuploidization factors have inherent relations, and how to prevent chromosome aneuploidy in aged oocytes. Epidemiologically, oocyte aneuploidy has been found to be weakly associated with higher homocysteine concentrations, obesity, ionizing radiation and even seasonality. In this review, we summarize the research progress and present an integrated view of oocyte aneuploidization.     

Telomere biology: Cancer firewall or aging clock?

It has been a decade since the first surprising discovery that longer telomeres in humans are statistically associated with longer life expectancies. Since then, it has been firmly established that telomere shortening imposes an individual fitness cost in a number of mammalian species, including humans. But telomere shortening is easily avoided by application of telomerase, an enzyme which is coded into nearly every eukaryotic genome, but whose expression is suppressed most of the time. This raises the question how the sequestration of telomerase might have evolved. The predominant assumption is that in higher organisms, shortening telomeres provide a firewall against tumor growth. A more straightforward interpretation is that telomere attrition provides an aging clock, reliably programming lifespans. The latter hypothesis is routinely rejected by most biologists because the benefit of programmed lifespan applies only to the community, and in fact the individual pays a substantial fitness cost. There is a long-standing skepticism that the concept of fitness can be applied on a communal level, and of group selection in general. But the cancer hypothesis is problematic as well. Animal studies indicate that there is a net fitness cost in sequestration of telomerase, even when cancer risk is lowered. The hypothesis of protection against cancer has never been tested in animals that actually limit telomerase expression, but only in mice, whose lifespans are not telomerase-limited. And human medical evidence suggests a net aggravation of cancer risk from the sequestration of telomerase, because cells with short telomeres are at high risk of neoplastic transformation, and they also secrete cytokines that exacerbate inflammation globally. The aging clock hypothesis fits well with what is known about ancestral origins of telomerase sequestration, and the prejudices concerning group selection are without merit. If telomeres are an aging clock, then telomerase makes an attractive target for medical technologies that seek to expand the human life- and health-spans.