Another Illustration as to Why There Will Be Many, Many Genetic Contributions to Longevity
As I mentioned not so long ago, there will most likely prove to be a great many subtle and overlapping genetic variants of human longevity. However, very few of them will be important in the sense that they will lead to ways to significantly increase human life span through new medicine. The effective way to greatly increase human longevity is to learn to repair the biochemical damage of aging, not to tinker with metabolism to slow down the rate at which damage occurs.
In any case, here is an excellent illustration as to why there will be thousands of genetic variations that contribute to human longevity: the effects on life expectancy of known single gene variants may be enhanced or diminished by other variations that do not themselves directly contribute to longevity. Combinations of genetic variants are probably just as important as single gene differences, in other words:
The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging....
Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. ... this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role.
We humans have a lot of genes, which means there is a very, very large number of potential interactions between gene variants - even within a subset of genes associated with a specific biological system. Discovery and understanding in the face of this complexity represents an enormous amount of work, which is one of the reasons that researchers who favor the metabolic manipulation approach to aging believe that we are a long way from any significant slowing of aging or extension of the healthy human life span.
This is why those of us who want to see that progress happen in our lifetimes should favor approaches like Aubrey de Grey's SENS: don't try to find, test, and debug ways to alter human metabolism, but rather work on repair technologies that can remove the known forms of biochemical damage that build up in the metabolism we have now.
Michal Jazwinski S, Kim S, Dai J, Li L, Bi X, Jiang JC, Arnold J, Batzer MA, Walker JA, Welsh DA, Lefante CM, Volaufova J, Myers L, Joseph Su L, Hausman DB, Miceli MV, Ravussin E, Poon LW, Cherry KE, Welsch MA, & for the Georgia Centenarian Study and the Louisiana Healthy Aging Study (2010). HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging. Aging cell PMID: 20569235