Aging differs from all human diseases by its complexity. It is the most complex phenotype currently known and the only example of generalized biological dysfunction. Its effects become manifest in all organs and tissues, it influences an organism's entire physiology, impacts function at all levels and increases susceptibility to all major chronic diseases. Nevertheless, typical symptoms of aging, often similar across species, can and have been defined.
For human aging, valuable information has been gleaned from a century of clinical observations. It was on this basis that, as mentioned earlier, a series of life-shortening genetic alterations in humans were described over a century ago that appeared to accelerate multiple signs of normal aging (Martin, 2005). These so-called segmental progeroid syndromes, already briefly discussed, were described by the medical community well before the discovery of DNA, and are therefore not biased toward a DNA-based hypothesis of aging. So it is remarkable that so many of these syndromes are defective in genome maintenance. The most striking of the human progeroid syndromes are Werner Syndrome (WS) (Epstein et al., 1965) and Hutchinson-Gilford Progeria Syndrome (HGPS) (Pollex and Hegele, 2004). WS is caused by a defect in a gene that is a member of the RecQ helicase family (Yu et al., 1996). The affected gene, WRN, encodes a RecQ homologue whose precise biological function remains elusive, but is important for DNA transactions, probably including recombination, replication, and repair.
HGPS is caused by a defect in the gene LMNA, which through alternative splicing encodes both nuclear lamins A and C (Eriksson et al., 2003). Nuclear lamins play a role in maintaining chromatin organization. Less striking segmental progeroid syndromes include ataxia telangiectasia, caused by a heritable mutation of the gene ATM (ataxia telangiectasia mutated), a relay system conveying DNA damage signals to effectors (Shiloh, 2003), Cockayne syndrome and trichothiodystrophy, diseases based on defects in DNA repair and transcription (Lehmann, 2003), and Rothmund Thomson syndrome, like Werner syndrome, based on a heritable mutation in a RecQ gene (Lindor et al., 2000). There is evidence that each of these genes when defective can also lead to aging symptoms in the mouse, sometimes in combination with other gene defects (see later, and Hasty et al., 2003).
Although in both humans and mice cancer incidence increases exponentially with age, the tumor spectrum in the two species differs significantly, with sarcomas and lymphomas predominant in the mouse and epithelial cancers in older humans (DePinho, 2000). Likewise, the spectrum of normal age changes (other than cancer) in mice and humans is not exactly the same, which always needs to be kept in mind when using these models (Hasty and Vijg, 2004). Moreover, although cancer as a phenotype is generally undisputed, aging has diffuse characteristics, and includes cancer and a variety of degenerative phenotypes (see www.niehs.nih.gov/ cmgcc/dbmouse.htm). Progeroid genotypes are associated with an early onset of some, but not all, characteristics of senescence and must therefore be interpreted with caution.
Loose criteria that help identify genuine mouse mutants of accelerated aging are (1) the phenotype should present after development and maturation are complete; (2) the phenotype should be demonstrable in control populations at a more or less similar point in their survival curve; and (3) the genetic alteration should accelerate multiple aging phenotypes (Hasty and Vijg, 2004). None of these criteria is written in stone. Indeed, accelerated aging can occur even before development is complete, as in the case of HGPS. Such cases, however, are more difficult to recognize as authentic models of aging and may not be as valid as those that exhibit aging phenotypes after maturation. It is also easily imaginable that a genetic alteration accelerates certain symptoms of aging much more than expected on the basis of the survival curve. Such so-called exaggerated aging would be expected if, rather than a quantitative, chronological master switch, the mutation would affect only one critical pathway for somatic maintenance leading to severe imbalance of the survival network.
Interestingly, the single-gene mutations that increase life span in worms, flies and mice may do so through the upregulation of cellular defense systems, including DNA repair and antioxidant defense. Candidate genes implicated in the control of such a survival response are FOXO and SIRT1, which have been demonstrated in nematodes and fruit flies to control downstream targets of the pro-longevity mutations affecting nutrient sensing, reproduction, and growth (Vijg and Suh, 2005). Down-regulation of these effector genes could then conceivably lead to an acceleration of all possible aging phenotypes. FOXO3a and SIRT1 knockout mice do not display apparent signs of accelerated aging, although it is possible that a progeroid phenotype will become visible after a more quantitative downregulation of these genes (Cheng et al., 2003; Hosaka et al., 2004).
It should be noted that the mutations that lead to increased longevity in nematodes, flies or mice are likely to do so only at the cost of some selective disadvantage, often not obvious under laboratory conditions (Jenkins et al., 2004). For some of the mouse longevity mutants, such as the growth hormone deficient Ames dwarf mice, fitness costs are readily apparent in the form of infertility and hypothyroidism (Bartke and Brown-Borg, 2004). However, for another longevity mutant in the mouse, p66SHC, there is no obvious selective disadvantage
(Migliaccio et al, 1999). At this time the only known consequence of deleting p66SHC is increased life span; thus, we presume the laboratory environment masks any disadvantage. For example, it is possible that p66SHC functions to increase cellular ROS to initiate cellular destruction as a part of our defense system against infectious agents. This potential disadvantage would be masked in the p66SHC-mutant mice since they are housed in a pathogen-free environment. We currently lack the detailed phenotypic comparisons to confirm that longevity-conferring mutations do so by retarding all possible symptoms of aging equally. Hence, though it is clear that mutations in single genes can activate survival pathways conferring increased longevity, the concept of master regulator genes to control the rate of aging is doubtful.
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For centuries, ever since the legendary Ponce de Leon went searching for the elusive Fountain of Youth, people have been looking for ways to slow down the aging process. Medical science has made great strides in keeping people alive longer by preventing and curing disease, and helping people to live healthier lives. Average life expectancy keeps increasing, and most of us can look forward to the chance to live much longer lives than our ancestors.