The biology of aging

4. Physiology of aging

Various animal model systems have been employed to dissect metabolic pathways involved in aging, among them the fruit fly Drosophila melanogaster, the worm Caernorhabditis elegans and the laboratory mouse Mus musculus. These organisms present several advantages: they are easy to grow and manipulate, their genetic background can be modified as needed and their DNA has been completely sequenced. Therefore, biologists have studied the effects of environmental stimuli and genetic mutations on the longevity of these model animals.
In worm and insects there is a direct correlation between metabolism and aging. Experimental manipulations of general metabolic levels and of oxidative stress (such as changes in temperature, nutrients and oxygen availability) have a profound effect on longevity.

Figure 2: Scheme of Insulin/IGF-1 signaling
The isolation of mutant animals with a prolonged life span has allowed the identification of specific genes involved in longevity. Most of these mutations alter the functions of the endocrine system. In mammals, insects and worms, the aging process can be modified by altering the Insulin/Insulin Growth Factor (Insulin/IGF-1)8 metabolic pathway. It has been observed that the inactivation of the Daf-2 gene (the receptor for Insulin/IGF-1) causes a prolonged life in animal models (about twice as long). This phenotype can be recapitulated also when regulatory genes within the Insulin/IGF-1 pathway are mutated. Such genes are mainly involved in general mechanisms of energy control and DNA repair. Therefore, one hypothesis is that the molecular functions of Insulin/IGF-1 have evolved initially to control survival. Indeed, Insulin/IGF-1 has the beneficial effect of promoting body growth and energy accumulation. When levels of insulin are reduced, life span is increased: the organism induces genes involved in stress responses and cellular energy is saved for maintenance of cellular integrity rather than growth.
Similarly, in yeast, a reduction of nutrients in culture medium causes an extension of life. This in vitro system can be considered a model of Caloric Restriction (CR) diet9,10. The effects of CR are mainly mediated by the activity of the SIR2 gene: SIR2 inactivation induces reduction of life span, while SIR2 over-expression increases longevity. In the worm Caernorhabditis elegans, the homolog of SIR2 displays the same features of the yeast gene. Therefore, SIR2 can be considered a master regulator of cellular longevity and aging. Its biochemical properties suggest that SIR2 might act as a ‘sensor’ of cellular metabolic state and might control life span according to cellular energy state.
A regimen of CR prolongs life of 50% also in laboratory mice. Genomic experiments have highlighted a multitude of genes induced in aged animals that are conserved in evolutionary distant species such as Caenorhabditis elegans and Drosophila melanogaster. Some of these genes encode for proteins involved in energy synthesis, mitochondrial functions and DNA repair. With similar techniques, biologists have discovered that aged mice under CR regimen displayed a gene expression profile similar to young mice.
Additional evidence can be added to the puzzle. A study conducted on members of the British aristocracy revealed that centenary women had fewer and later pregnancies as compared to women that die at a younger age. This observation is confirmed in nature in wild mammals and birds, where longevity and fecundity are inversely correlated. When the germline is removed from the worm Caenorhabditis elegans, life span is prolonged of about 60%. In experimental mice, ovary transplant from young to old females extends average life expectancy of about 40-60%. Thus, biological mechanisms may regulate life span according to fertility. In fact, CR regimen can increase longevity and reduce fertility, as demonstrated in insects, worms and rodents. It is then reasonable to hypothesize that, under conditions not favorable for reproduction, it is of major advantage to dislocate energy consumption from reproduction to survival.

8 Kenyon, C. (2005): “The plasticity of aging: insights from long-lived mutants, Cell, no. 25, 120 (4), pp. 449-60.
9 Guarente, L. and Picard, F. (2005): “Caloric restriction — the SIR2 connection”, Cell, no. 25, 120(4), pp. 473-482.
10 McCay, C.M., Cromwell, M.F. and Maynard, L.A. (1935): “The effect of retarded growth upon the Length of life span and ultimate body size”, J. Nutr, no. 10, pp. 63-79.

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