Slowing the aging process, and thereby extending life, has been a human goal throughout recorded history and probably in preliterate times as well. The marked increase in human life expectancy in the 20th century could be viewed as achieving this goal. However, much of that increase results from prevention of premature deaths related to infections and other environmental hazards. It remains to be established how much, if any, of the increase relates to slowing the aging process. Indeed, over the centuries, the life span of the oldest of the old in human populations has changed little, although the fraction of the population reaching these advanced ages has increased significantly. In contrast, both environmental and genetic manipulations can markedly extend the maximal life span of a population in several other species.
Caloric restriction slows aging and extends life in several species, including some mammals
Restricting the food intake of rats, starting soon after weaning, increases both mean and maximum life span of both genders of several strains of rats—as first reported by Clive McCay in 1935. N62-18 The marked increase in rat longevity is graphically illustrated by the survival curves in Figure 62-7. Manipulation of the components (protein, fat, carbohydrate, minerals, and vitamins) of a purified rat diet revealed that the life-extending action of food restriction in rats results from caloric restriction rather from than a specific dietary component.
FIGURE 62-7 Survival curves for a population of 115 male F344 rats fed ad libitum and 115 male F344 rats with restricted food intake (i.e., 60% of the ad libitum intake) starting at 6 weeks of age. Note that both the median length of life and the maximum length of life are markedly greater in the restricted population. (Data from Yu BP, Masoro EJ, Murata I, et al: Life span of SPF Fischer 344 male rats fed ad libitum or restricted diets: Longevity, growth, lean body mass, and disease. J Gerontol 37:130–141, 1982. Copyright The Gerontological Society of America. Reproduced by permission of the publisher.)
For information on the scientific papers of Clive McCay (1920–1967), visit http://rmc.library.cornell.edu/EAD/htmldocs/RMA01087.html (accessed February 2015).
Reducing food intake also extends the life of mice, N62-19 hamsters, dogs, fish, several invertebrate animal species, and yeast. Studies of rhesus monkeys, still in progress, indicate that food restriction may also extend the life of nonhuman primates.
Effects of Caloric Restriction in Mice
Contributed by Edward Masoro
A recent study by James Nelson and colleagues, in which 41 inbred mouse strains were used, indicates that caloric restriction–induced life extension in different mouse genotypes is less common than heretofore believed. Determining how common it is among species for caloric restriction to extend life will require much more research.
Liao CY, Rikke BA, Johnson TE, et al. Genetic variation in the murine lifespan response to dietary restriction: From life extension to life shortening. Aging Cell. 2010;9:92–95.
Does food restriction extend life by slowing aging processes? This is a difficult question to answer because of the lack of consensus on how to measure the aging of individuals or populations. However, for two reasons, most biogerontologists believe that food restriction does retard aging processes. First, compared to rodents of the same age fed ad libitum, those on life-extending food-restriction regimens maintain physiological processes more like those of young animals. Second, life-extending food restriction delays the onset or progression of most age-associated diseases, including neoplastic, degenerative, and immune diseases.
During the past 70 years, many hypotheses have been proposed regarding the biological mechanisms underlying the life-prolonging action of food restriction, but none is firmly established. McCay proposed that caloric restriction extends life by retarding growth. However, later observations showed that food restriction, even when initiated in young adult rats or middle-age mice, significantly extends life. Another early hypothesis was that food restriction extends life by markedly reducing adipose fat mass. However, it is possible to dissociate the effects of food restriction on longevity from the effects on fat mass in rats and mice.
Currently, the most popular view is that food restriction extends life by decreasing oxidative stress (see pp. 1238–1239). Indeed, life-extending food restriction does decrease the accumulation of age-associated oxidative damage. It also causes a sustained reduction in plasma glucose levels, which could reduce glycation and glycoxidation (see p. 1239), as well as a marked and sustained reduction in plasma levels of insulin and IGF-1. Genetic studies strongly indicate that decreasing insulin-like signaling (see pp. 996 and 1041–1042) extends life. Thus, the decrease in the levels of insulin and IGF-1 may well play an important role in food restriction–induced life extension.
Inhibiting the mTOR pathway (see Fig. 51-6) by administering rapamycin extends the life of 600-day-old mice. N62-20 This mTOR pathway senses nutrient status and is involved in regulating eukaryotic growth and cell division. Thus, it is possible that inhibiting the TOR pathway has a role in caloric restriction–induced life extension.
TOR Kinases and the Aging Process
Contributed by Edward Masoro
To survive, organisms must be able to respond to variable nutrient availability by transitioning between anabolic and catabolic status. The mTOR (mechanistic target of rapamycin) protein kinase systems play a major role in enabling organisms to do so. Rapamycin—which is produced by a soil bacterium and has antifungal, anticancer, and immunosuppressive actions—inhibits mTOR protein kinases.
In mammals, mTOR is found in two multiprotein complexes: mTORC1 and mTORC2. The protein components of mTORC1 are mTOR, Raptor (scaffold protein), Pras 40 (mTORC1 inhibitor), Deptor (mTOR inhibitor), mLST8 (function unknown), and tti1 and tel2 (stability and assembly proteins). The components of mTORC2 are mTOR, Rictor (scaffold protein), mSn1 (scaffold protein), Protor 1/2 (assists in activation of SGK1), Deptor, mLST8, tti1, and tel2.
The activity of mTORC1 is promoted by amino acids, energy level, growth factors, and oxygen and is inhibited by stress. In turn, mTORC1 promotes growth, cell-cycle progression, macromolecular biosynthesis, and metabolism, and inhibits autophagy.
The activity of mTORC2 is promoted by growth factors. In turn, mTORC2 promotes metabolism, cytoskeletal organization, and cell survival.
These actions of the TOR complexes involve a spectrum of signaling pathways and are the subject of continuing research.
It was long held that rapamycin inhibits only the activity of TORC1. However, it is now clear that the sustained use of rapamycin also inhibits TORC2, which complicates the interpretation of studies based on the actions of this inhibitor.
That TOR may play a role in aging was first suggested in 2003 when Vellai and colleagues reported that a deficiency of TOR kinases more than doubles the life span of C. elegans. A year later, Kapahi and coworkers reported that inhibiting TOR kinases extends the life span of Drosophila. And in 2005, Kaeberlein and colleagues reported that deletion of TORC1 increases the replicative life span of yeast. In 2009, Harrison and colleagues reported that rapamycin fed to genetically heterogeneous mice starting late in life (600 days of age) extended the life span by 14% in females and 9% in males.
In a recently published study, Lamming and coworkers hypothesized that rapamycin extends the life span of females more than that of males because it inhibits both TORC1 and TORC2. Indeed, when they decreased or eliminated the Rictor component of TORC2 in mice by any of three different procedures, they found that the life span was significantly decreased in male mice but was not affected in female mice.
Although much more remains to be learned about the role of TOR kinases in aging, it is clear that, via their signaling networks, they play important roles in the aging process. Studies aimed at defining these networks in relation to aging almost certainly will be a major focus of future biogerontological research.
Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends the life span in genetically heterogeneous mice. Nature. 2009;460:392–395.
Kaeberlein M, Powers RW, Steffen KK, et al. Regulation of yeast replicative life span by TOR and Sch 9 in response to nutrients. Science. 2005;310:1193–1196.
Kapahi P, Zid BM, Harper T, et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004;14:885–890.
Lamming DW, Mihaylova MM, Katajosto P, et al. Depletion of Rictor, an essential protein component of TORC2, decreases male lifespan. Aging Cell. 2014;13:911–917.
Lamming DW, Ye L, Katajisto P, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335:1638–1643.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274–293.
Vellai T, Takacs-Vellai K, Zhang Y, et al. Influence of TOR kinase on lifespan in C. elegans. Nature. 2003;426:620.
Another theory of the antiaging action of caloric restriction is hormesis, defined as the beneficial effects resulting from cellular responses to mild repeated stress, which would stimulate maintenance and repair processes and thereby retard aging. Food restriction at the level that extends life is a mild stress repeated daily. Moreover, food-restricted rodents have an increased ability to cope with acute, intense damaging agents, such as surgery, toxic chemicals, and high environmental temperatures.
Genetic alterations can extend life in several species
Caloric restriction is an example of environmental factors that determine longevity. It is also clear that genetics has a major role. For example, the large differences in life span among species (from <100 days in Drosophila melanogaster to <5 years in mice to >100 years in humans) are primarily, if not exclusively, due to genetic differences. Moreover, selective breeding within a species can produce populations that differ significantly in longevity.
Longevity probably depends on multiple genes. Thus, it was a surprise when Friedman and Johnson reported in 1988 that mutation of the age-1 gene of the nematode worm, Caenorhabditis elegans, results in a marked increase in longevity. The age-1 gene encodes a phosphatidylinositol 3-kinase (see p. 1042), which is a component of the insulin-like signaling pathway. Note that C. elegans, like other invertebrates, does not have separate signaling pathways for insulin (see pp. 1041–1042) and IGF-1 (see p. 996), as do mammals. The mutation of age-1 studied by Friedman and Johnson causes some loss of function—that is, it is a weak mutation. Among other single-gene manipulations found to extend the life of C. elegans, D. melanogaster, Saccharomyces cerevisiae, and mice, many but not all involve a partial loss of function of the insulin-like signaling pathway.
Ames dwarf mice have a recessive point mutation in the Prop-1 gene, which results in the inability of the pituitary to produce GH, TSH, and prolactin. These mice have low levels of thyroid hormone, IGF-1, and insulin. Significantly, these dwarf mice have an increased life span compared with littermates not homozygous for this mutation.
Further support for a role of reduced insulin-like signaling in life extension comes from studies of mice with a knockout of the GHR/BP gene, which encodes the GH receptor and its proteolytic cleavage product, GH-binding protein. This knockout mouse exhibits growth retardation, high plasma GH levels, low plasma IGF-1 levels, and significant life extension. Reducing the expression of the insulin receptor by 85% to 90% in the adipose tissue of mice resulted in significant life extension. Finally, overexpression of the KLOTHO gene N36-12 in mice increases the plasma level of Klotho protein, which suppresses insulin and IGF-1 signaling and extends the life of mice.
In yeast, overexpression of the sir2 gene increases the level of a sirtuin protein called Sir2 and extends the replicative life of S. cerevisiae. Sir2 is a deacetylase that stabilizes ribosomal DNA. Sir2 may play a role in other species. Indeed, stimulating Sir2 orthologs extends the life span of C. elegans, D. melanogaster, and human cell lines. However, it is not yet clear whether sirtuin proteins play an important role in the life-prolonging action of caloric restriction.
Proposed interventions to slow aging and extend human life are controversial
We have already seen that life-extending dietary manipulations, pharmacological interventions, and genetic alterations may have in common that they modify signaling pathways. Because these signaling pathways probably interact extensively, it is attractive to speculate that they are components of a longevity-signaling network.
The practice of antiaging medicine is becoming popular and plays an important role in preventing the occurrence and progression of certain age-associated diseases. For example, exercise and diet can reduce the incidence of coronary heart disease, stroke, and type 2 diabetes. However, some practitioners of antiaging medicine, as well as suppliers of pharmaceuticals and nutraceuticals, claim to have “magic bullets” that slow or even reverse aging. These purported magic bullets include antioxidants (e.g., vitamins E and C), amino acids (e.g., methionine), drugs (e.g., deprenyl), and hormones (e.g., melatonin, dehydroepiandrosterone, GH, estrogen, and testosterone). No credible evidence indicates that any of these agents will reverse or even slow human aging. Aside from the question of efficacy is the possibility of long-term adverse effects of these supposed magic bullets. Combined estrogen and progestin therapy is a case in point. Although hailed for relieving the symptoms of menopause, this hormone replacement therapy was long in use before a well-designed study uncovered its harmful effects on the cardiovascular system. In light of the animal studies strongly indicating that insulin-like signaling promotes aging, the current use of recombinant GH is of concern. Although GH increases lean body mass in the elderly, well-designed studies are needed before GH is used as an antiaging agent.