Arguing for Autophagy as the Primary Mechanism by which Exercise and Calorie Restriction Improve Health and Longevity
Autophagy is the name given to a collection of maintenance and recycling mechanisms responsible for removing damaged and unwanted proteins and structures from within cells. Many of the means of modestly slowing aging demonstrated in laboratory species feature increased levels of autophagy, in in some cases that increase in autophagy has been shown to be necessary for benefits to result. That autophagy is the most important means by which beneficial stresses such as exercise and calorie restriction improve health and longevity is by no means a novel argument. It has been made for decades, with increasing confidence.
Despite this, there has been comparatively little progress when it comes to the development of therapies that directly target the operation of autophagy, as opposed to calorie restriction mimetics that do so indirectly by targeting regulators known to be involved in the calorie restriction response. (We could argue about which side of that line mTOR inhibitors fall on, but their connection to aging arose out of work on calorie restriction rather than work on autophagy per se). In part this is because safely manipulating the state of metabolism is very challenging; metabolism is enormously complex and still comparatively poorly mapped.
Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age-related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidence suggests that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality.
Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy-dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise-induced TORC1 and autophagy signaling share common pathways with that of CR.
Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity.
Apollo Ventures has a portfolio company focused on geroprotector screening and one of the key areas of interest in autophagy enhancement.
Here is a brand new review on autophagy and aging:
https://www.nature.com/articles/s41556-018-0235-8
@Sebastian Aguiar: David Sinclair's Life Biosciences also has an autophagy enhancement focused portfolio company as I recall. It will be interesting to see if we see any real motion in this line of work in the next few years, as all too little progress towards commercialization has so far taken place. A little odd given the sizable amount of research into modulation of autophagy over the past twenty years.
Do we have any data showing AD as a manifestation of reduced autophagy ? If so, NAD enhancers such as Tru Niagen could serve to stimulate autophagic removal of beta Amyloid and Tau ? At the age of 80 I have more than a passing interest in this topic.