One important precept of evolutionary theories of aging is the painfully simple observation that events occurring after an organism’s death (whether due to intrinsic factors or extrinsic ones like predation) are hidden from natural selection. Therefore, there is no way to select against deleterious traits that would have been expressed only after the end of the natural lifespan. Consequently, eliminating a single longevity-limiting factor will likely reveal another longevity-limiting factor that acts later (or alternatively, throughout the lifespan but more slowly).

The bad news: There will be no magic bullet.

The good news: At least in the case of pathways that govern rates of aging, it is likely that combinations of multiple genetic interventions and treatments will have an additive or even synergistic effect on longevity.

A fairly heroic example of this comes from Wei et al., who deleted two yeast genes involved in separate pathways that restrict longevity, and then calorie-restricted the resulting mutants. This combination of interventions resulted in cells that enjoy a chronological lifespan ten times longer than wild-type yeast. The authors also describe a kinase and several associated genes (including stress-responsive transcription factors) required for this record-breaking lifespan extension:

Calorie restriction-induced life span extension depends on Rim15 and stress response transcription factors downstream of Ras/cAMP/PKA, Tor and Sch9

Calorie restriction, the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension associated with the deficiencies in Tor and Ras signaling, and show that it is also required for the longevity promoting effect of both extreme (water) and standard (0.5% glucose) calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. Surprisingly, the lack of Rim15 only partially decreased the 10-fold life span extension caused by the combination of CR and the deletion of both RAS2 and SCH9/AKT. These results suggest that Rim15 functions as a central regulator of stress resistance and longevity downstream of the Ras/cAMP/PKA, Tor and Sch9 pathways during calorie restriction. Transcription factors Msn2, Msn4, and Gis1 are also important for Rim15-dependent life span extension but that additional mediators are involved.

While results of this kind are subject to a host of qualifications about whether lifespan determination in free-living single-celled fungi resembles that of multi-cellular organisms, there is some reason to believe that these yeast data are unusually germane to human longevity: According to senior author Valter Longo, there exist human populations with loss-of-function mutations in the homologs of the genes Wei et al. knocked out in the yeast study — and while these humans are not exactly normal, they appear to be significantly resistant to cancer (see this article, which contains an interview with Longo, for more details). The Longo lab is currently investigating whether the human mutations confer resistance to other age-related disease or an overall increase in longevity.

(Hat tip to Eric for alerting me to these findings.)