Fight Aging!

Most research into intervening in the aging process is focused on slowing aging. It is a search for ways to safely alter metabolism in order to reduce the rate at which unrepaired cellular and molecular damage accumulates. This damage is a side-effect of the normal operation of metabolism, and it in turn leads to chains of further changes and damage, and all of that together causes aging - a progressive dysfunction and rising risk of catastrophic system failure in organs and tissues based on growing levels of damage. Working on ways to slow aging is the dominant strategy in the mainstream not because it is the best way forward, but rather because it involves exactly the same research process as is employed in the established drug development pipeline: researchers work on explaining how a tiny slice of metabolism works, find a way to alter it in the existing drug library or develop a new drug for that purpose, and then see if it has a positive enough outcome to move towards trials.

Based on results to date it is highly unlikely that this convenient approach will do much more than add knowledge and consume funding. It is not going to result in ways to greatly extend human life spans in the near future: a decade and at least a billion dollars spent on research of the molecular biology of life extension via calorie restriction has demonstrated just how hard it is to use drugs to replicate even this easily replicated and very well studied method. Despite the time and effort calorie restriction is still not yet fully understood, and there is no reliable drug candidate to mimic even a fraction of its effects on health and longevity at this point. Metabolism is exceedingly complex, and so is the calorie restriction response. Even if a perfect calorie restriction mimetic drug turned up tomorrow, which it won't, then would this drug help old people? From the point of view of extending healthy life, not really. There is little use in a drug that slows down the rate at which damage accrues if you are already elderly, frail, and extremely damaged.

The research community should be focused instead on rejuvenation. Repair the damage in the metabolism we have and restore it to the known good working state it exhibits in youth. Don't slow down the damage, try to fix it: help the elderly and frail by restoring youthful function to their tissues. Metabolism complex and changing it would be enormously challenging, so don't change it. The damage that accumulates in and between our cells due to the operation of metabolism is very simple by comparison. Its effects, the aging process, are only complex because we are complex: simple damage in a complex system produces complex results. Consider this: no-one would rebuild an engine to make it work better when it is very rusted, as it is obviously better to remove the rust and rust-proof that machinery. The former option is enormously complex and ultimately doomed to produce only marginal benefits, while the latter is much simpler and restores the engine to an earlier level of function and a longer expected working life span. Rust is simple, engines are complex.

There is far too much engine rebuilding going on in medical research today, and not enough of a focus on the rust. This must change if we are to see meaningful progress towards bringing aging under medical control in our lifetimes. There is a lot of inertia in the present research community and its establishments, however. I expect to see the drug discovery and metabolic alteration approach to slowing aging continue on its largely futile way for decades, even as the better approach to treating aging gathers support and overtakes it. One of the obvious targets in addition to mimicking the benefits of calorie restriction is to try to enhance cellular housekeeping processes responsible for repairing many forms of molecular and cellular damage. Evidence strongly suggests that many of the ways demonstrated to slow aging in laboratory animals are at least partially due to increased levels of cellular housekeeping. So research results like this paper below appear regularly these days:

Inducing Muscle Heat Shock Protein 70 Improves Insulin Sensitivity and Muscular Performance in Aged Mice

Heat shock proteins (HSPs), named after the observed up-regulation following heat shock, are a family of protective chaperone proteins that maintain normal cellular function when cells are under various stressors. Aging is associated with generally reduced levels of heat shock protein 70 (HSP70), which plays a conserved role in cellular homeostasis in all species. Genetic manipulation to increase generalized HSP70 levels has improved lifespan in invertebrate models, and thus it is the focus of our studies. It has been demonstrated that aged muscle tissue does not increase HSP production in adaptation to normal exercise; however, increases in muscle mass and function can be generated by pharmacological induction or overexpression of HSP70.

Aged C57/BL6 mice acclimated to a western diet were randomized into: geranylgeranylacetone (GGA)-treated (100mg/kg/d), biweekly heat therapy (HT), or control. The GGA and HT are well-known pharmacological and environmental inducers of HSP70, respectively.

HT mice had more than threefold, and GGA mice had a twofold greater HSP70 compared with control. Despite comparable body compositions, both treatment groups had significantly better insulin sensitivity and insulin signaling capacity. Compared with baseline, HT mice ran 23% longer than at study start, which was significantly more than GGA or control. Hanging ability (muscular endurance) also tended to be best preserved in HT mice. Muscle power, contractile force, capillary perfusion, and innervation were not different. Heat treatment has a clear benefit on muscular endurance, whereas HT and GGA both improved insulin sensitivity. Different effects may relate to muscle HSP70 levels. An HSP induction could be a promising approach for improving health span in the aged mice.

Will useful therapies will result from this sort of thing? Likely so: some interesting and fairly dramatic results have been obtained by boosting the operation of cellular housekeeping mechanisms over the years. But this isn't the road to bringing aging under medical control and greatly extending healthy life spans, for the reasons noted above. Slowing aging isn't good enough, being only an expensive path to poor results in terms of healthy years of life gained and the ability to rejuvenate the old.