Fight Aging!

Mechanically speaking, degenerative aging happens for the same underlying reasons in all of us. We all share the same operation of cellular metabolism, generating the same lingering waste products, the same forms of biochemical wear and tear that slowly slip past otherwise comprehensive repair mechanisms. It's all damage, and aging is in effect just a process of damage accumulation. Our organs and tissues react to that damage and waste in the same ways, so much so that you can use patterns of epigenetic markers of cell state to identify age, pulling that out from all of the thousands of changes in cell state that are distinct to a person's unique environment and circumstances.

There is a lot of interest today in identifying the genetic differences and metabolic processes that react to environmental circumstances to determine natural variations in aging and longevity in our species. Some people think that this is the way to produce therapies to extend healthy life spans: figure out what makes some people more likely to live to 100, say a 1% chance rather than a next to 0% chance, and implement some kind of drug that affects similar changes in ordinary people. Take Human Longevity Inc., for example, as representative of the viewpoint of a sizable research contingent. This all seems like a short-sighted approach to me. You're tinkering around in the reaction to the underlying cause of aging, while failing to address the actual problem - which is the damage that causes these reactions. It's like trying to make cars fall apart less frequently by working on oil formulations. There's a much better approach to making cars fall apart less frequently, and that's to repair them every so often. If you don't carry out periodic repair, you aren't going to get much out of better oil. It all seems backwards in a way.

You can make a bunch of money mining, analyzing, and selling genetic data. Human Longevity Inc. will no doubt do just fine as a business, and along the way add to human knowledge in a useful way that incrementally advances the general state of medicine. This just isn't the path to near term meaningful extension of human life spans. It's heading off in entirely the wrong direction for that, missing the forest for the trees, and the same can be said for much of the rest of the research community. They are very focused on mapping aging and its biochemistry in all of its present variations, and largely disinterested in fixing the damage that causes all of this glorious biological complexity. And pain, and suffering, and death. It's the pain and suffering and death on a vast scale that makes this something other than an academic matter in which the research community can be indulged in their desire to produce a complete map of the situation.

In any case, here is an example of the point that aging has root causes, and many age-related conditions spring from the same root causes. There are thousands of failure modes for damaged tissues, but back down the chain of cause and consequence only a handful of those root causes. This is written from the perspective of those who see intervention in the reactions to damage as the way forward, rather than those who look to repair of damage as the way forward - which is to say it is written from the present mainstream view, not the view that needs to supplant it if we are to see meaningful progress in the near future.

Genetic evidence for common pathways in human age-related diseases

It is widely accepted among gerontologists that common processes mechanistically underlie both aging and the pathogenesis of multiple age-related diseases and that targeting common factors in aging will have a significant benefit to human health. A wealth of experimental data from lower organism studies supports this concept, and human progeroid syndromes indicate that disruption of key biological processes can result in the premature onset of multiple age-related pathologies. There has, however, been little direct evidence that this is true in normal human aging and age-related disease, and the role of canonical aging pathways in human age-related pathologies has not been established.

Our gene-based findings suggest that while inflammation, immune regulation, and cholesterol metabolism are all broadly important in human aging, cholesterol metabolism genes alone are strikingly enriched among multiple age-related diseases. Multiple apolipoproteins have been associated with disease, and APOE is a particularly notable genetic loci in human health, as discussed. Consistent with these prior findings, our data suggest that apolipoprotein metabolism is a key underlying pathway in multiple human age-related diseases. Our findings suggest that apolipoprotein metabolism may represent a mammalian-specific underlying pathway in aging and age-related disease, supporting the notion that interventions in lipoprotein metabolism will provide significant benefits to human health. Epidemiological studies already support the adoption of earlier and more widespread statin use, and least one study has suggested that statins broadly affect the aging process. Clearly, apolipoprotein metabolism warrants continued attention as a safe and efficacious clinical target in aging.

In addition to providing further evidence supporting the critical importance of apolipoprotein metabolism in human age-related disease, here, we provide evidence supporting for the model that common, evolutionarily conserved pathways influence many age-related diseases. The data presented here provide new evidence supporting the continued pursuit of interventions designed to combat age-related disease based on genetic pathways of aging discovered in lower organisms. While many of these pathways, such as genome maintenance and IIS/mTOR signaling, have already been implicated in human health, our study provides the first evidence that genome-wide association studies of age-related diseases show a signature of conserved pathways of aging. Finally, while our study focused on age-related disease, our novel pathway-based approach provides a new method for identifying shared pathways of disease. We anticipate that this approach can be applied to traits that are mechanistically poorly defined to provide novel insight into the pathogenesis of human diseases.