Fight Aging!

Common genetic variants contribute to individual differences in longevity when considered statistically across thousands of individuals and decades of their lives. But even statistically common genetic variations are not particularly important until later life. For all but a few unlucky individuals with rare genetic conditions, the difference between comparative health and comparative frailty at the end of middle age is a matter of lifestyle choices and environment, not genes. After that, however, genetics becomes increasingly important as an influence. It is important to realize that, again, this is only when considered statistically. For every centenarian with a given genetic variation there are scores of other individuals with that very same variant who died at much younger ages. Odds of survival that are improved from 1% to, say, 1.5% remain terrible odds.

The dominant theme emerging from research into the genetics of longevity within our species is that individual variants have very small effects. Further, most statistical associations between specific genetic differences and human longevity are not replicated when studies are repeated with different populations. This tends to be true even for different study populations in the same region - see a recent investigation of associations between FOXO3A and longevity for a good example of this outcome. So in addition to being small, effects are very complicated and highly variable between even very similar genetic lineages. At present there are really only two good associations discovered to date, variants of APOE and FOXO3A, and even these are hard to extract from the data at times.

The situation is somewhat better when it comes studies of age-related conditions and genetics. There are a wide range of robust associations for various conditions in which certain genetic variants seem to imply a lower resistance to specific disease processes that occur in everyone. Investigating the biochemistry of a disease tends to turn up candidate genetic variants in the process of obtaining a better understanding of what exactly is going wrong. You might look at what is known of genetic associations with Parkinson's disease for a good example of how this tends to work out in practice.

To further complicate things, most work in biology and medicine doesn't start with humans, and this is especially true of longevity science. People, mice, flies, worms, and even yeast are all part of the same evolutionary tree and share a surprising number of genes and mechanisms relating to the intersection of metabolism and longevity - which is where you'll most likely find the engines driving natural variations between individuals, as well as the fine details of the ongoing progressive global systems failure that is aging. This common evolutionary heritage is why researchers can obtain insights into human aging and metabolic processes from yeast and flies, and if that can be done it is certainly a whole lot cheaper than trying the same wait and see studies in people.

This doesn't mean that any of this is straightforward, however. People are not mice, and considerably progress in finding longevity-associated genes and single gene mutations that reliably extend life in rodents has not yet led to any similar advances in a coherent mapping of the human genetics of longevity. This short note on the topic is from the lead at one of the groups involved in sequencing the bowhead whale genome in search of explanations for its lengthy life span, thought to be in excess of two centuries:

Why genes extending lifespan in model organisms have not been consistently associated with human longevity and what it means to translation research

A recent paper reports the largest genome-wide association study of human longevity to date. While impressive, there is a remarkable lack of association of genes known to considerably extend lifespan in rodents with human longevity, both in this latest study and in genetic association studies in general. Here, I discuss several possible explanations, such as intrinsic limitations in longevity association studies and the complex genetic architecture of longevity.

Yet one hypothesis is that the lack of correlation between longevity-associated genes in model organisms and genes associated with human longevity is, at least partly, due to intrinsic limitations and biases in animal studies. In particular, most studies in model organisms are conducted in strains of limited genetic diversity which are then not applicable to human populations. This has important implications and, together with other recent results demonstrating strain-specific longevity effects in rodents due to caloric restriction, it questions our capacity to translate the exciting findings from the genetics of aging to human therapies.

Of the 51 gene manipulations extending lifespan in mice, how many would still extend lifespan in genetically heterogeneous mice and by how much? How many would be detrimental? When considering potential applications of the genetics of aging one should keep in mind that these have not been replicated in humans and that even in model organisms these are derived from a very small selection of clones that do not represent the whole species.

For me this is one more item to add to the great mountain of evidence telling us that manipulation of genetics and the operation of metabolism so as to slow aging simply isn't the right path forward. It is too hard, too slow, an attempt to alter an enormously complex and poorly understood system in non-trivial ways, and has too poor an outcome even if successful in comparison to other strategies. Slowing aging can't help the old, and it would be a real shame if all of the effort and investment of the next few decades leads only to therapies that do little for the young and nothing for those of us who helped to bring them about.

To move rapidly towards treatments for aging we should look at cataloging the differences between young tissues and old tissues, determine which of those differences are fundamental and primary, not caused by any of the others, and build the means to revert those differences. The state of knowledge about aging is far further advanced towards that goal than towards a goal of safe metabolic re-engineering.