The Influence of Genes on the Aging Process of Mice: A Statistical Assessment of the Genetics of Aging

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ABSTRACT

Genetic interventions that accelerate or retard aging in mice are crucial in advancing our knowledge over mammalian aging. Yet determining if a given intervention affects the aging process is not straightforward since, for instance, many disease-causing mutations may decrease life span without affecting aging. In this work, we employed the Gompertz model to determine whether several published interventions previously claimed to affect aging in mice do indeed alter the aging process. First, we constructed age-specific mortality tables for a number of mouse cohorts used in longevity experiments and calculated the rate at which mortality increases with age. Estimates of age-independent mortality were also calculated. We found no statistical evidence that GHRHR, IGF1R, INSR, PROP1, or TRX delay or that ATM + TERC, BubR1, klotho, LMNA, PRDX1, p53, WRN + TERC, or TOP3B accelerate mouse aging. Often, changes in the expression of these genes affected age-independent mortality and so they may prove useful to other aspects of medicine. We found statistical evidence that C/EBP, MSRA, SHC1, growth hormone, GHR, PIT1, and PolgA may influence aging in mice. These results were interpreted together with age-related physiological and pathological changes and provide novel insights regarding the role of several genes in the mammalian aging process.

ALTHOUGH aging is a major biological problem, the mechanisms involved are largely a mystery. One essential tool in understanding the biological basis of aging is the manipulation of the aging process in animal models. Namely, genetic interventions that accelerate or retard aging in mice are crucial in advancing our knowledge over the genetic and molecular mechanisms of mammalian aging (LIANG et al. 2003; HASTY and VIJG 2004; QUARRIE and RIABOWOL 2004). Several interventions, including mutations, have been reported to increase or decrease life span when compared to wild-type controls (Table 1). Yet determining if these interventions accelerate or delay aging is not straightforward since, for instance, many disease-causing mutations may decrease life span without affecting aging. Therefore, for genetic interventions to enhance our knowledge over aging it is crucial to discriminate between interventions affecting the aging process and interventions affecting health, as proposed by many others (WILLIAMS 1999; HAYFLICK 2000; PLETCHER et al. 2000).

To ascertain whether aging changed or not due to a given intervention, one approach is to determine whether the pace of age-related changes and/or the onset of age-related pathologies has shifted (e.g., KURO-O et al. 1997; MILLER 2001). Another approach is to calculate the rate at which mortality increases with age, which is a normal outcome of aging in most species (PLETCHER et al. 2000). Using the Gompertz equation it is possible to calculate the mortality rate doubling time (MRDT; FINCH 1990, pp. 22-24; MUELLER et al. 1995). Caloric restriction (CR) in rodents, for example, fulfills both these criteria since it roughly doubles the MRDT and delays age-related debilitation (WEINDRUCH and WALFORD 1988). Unfortunately, details of age-related changes and MRDT calculations are rarely available in genetic interventions affecting longevity in mice and so researchers often assume that a change in longevity is representative of a change in the aging process when such may not be the case. Instead, changes in agingindependent mortality may be the cause of a shortened or lengthened life span (FINCH 1990, pp. 22-25). For example, cancer-promoting genes may decrease life span in mice by increasing cancer rates without affecting aging (DONEHOWER et al. 1992).

In this work, we first wanted to evaluate the Gompertz model to study aging in mice, particularly since such experiments often involve small cohorts. Afterward, we wanted to determine whether several published genetic interventions affecting longevity in mice that have hinted to influence aging do indeed affect the aging process. …