A Continued Focus on Autophagy in Clinical Development
Evidence suggests that improved autophagy is the most important mechanism by which calorie restriction and other mild stresses produce slowed aging and extended life in lower animals and mammals. Disabling autophagy prevents calorie restriction from lengthening life span in laboratory species. Autophagy is the collection of processes responsible for recycling damaged proteins and cell structures. One might think, in a simple model of the situation, that keeping molecular damage to a low ebb over time reduces secondary consequences of that damage and consequent loss of function. We might look at cellular senescence as one of those secondary consequences. Certainly, the evidence suggests that calorie restriction and pharmacological approaches to improve autophagy such as mTOR inhibition reduce the pace at which cells become senescent and thus lowers the harmful burden of senescent cells in older individuals.
The mTOR inhibitor rapamycin and calorie restriction are both modestly better than exercise when it comes to extending life span in short-lived species, which is a decent reason to believe that developing drugs to upregulate autophagy is a worthwhile pursuit. The positive effects of exercise on late life health and life expectancy remain the low bar to beat for academia and industry. Few approaches have managed this to date.
There are two points to consider that make this all somewhat less clear cut, however. Firstly, it is well established that calorie restriction, and other forms of mild stress leading to upregulation of cellular maintenance processes such as autophagy, have diminishing effects on life span as species life span increases. Mice can live up to 40% longer on a low calorie diet. Humans most certainly cannot, and while the actual number is unknown, it seems unlikely that decades of sustained calorie restriction in humans can add more than a few years of life. Why this is the case when the short-term benefits to health and metabolism are quite similar remains a open question.
Secondly, one of the more noteworthy ways in which autophagy cleans up damage in the cell is to recycle worn and damaged mitochondria. Mitochondrially targeted autophagy is known as mitophagy. Every call contains hundreds of mitochondria engaged in the production of chemical energy store molecules, but the mitochondrial population becomes less efficient with age. Evidence points to failing mitophagy, either because autophagic mechanisms in general are faltering, or because changes in mitochondria prevent the efficient application of mitophagy to damaged mitochondria. A whole range of pharmacological approaches to improving mitochondrial function appear likely to produce benefits by improving mitophagy - but none of these appear to improve on the effects of exercise. Drugs and supplements that improve mitophagy, perhaps indirectly by altering mitochondrial dynamics, don't appear to be as good as those that directly upregulate autophagy. That is a bit of a puzzle given the consensus on the importance of mitochondria to aging.
None of these questions are in any way going to slow down an industry that is largely focused on producing small molecule therapies that adjust metabolism for some small benefit. Autophagy and mitophagy are widely appreciated targets, and the industry is biased towards a system in which the primary goal is to find new small molecules for established target mechanisms that are slightly better than the existing small molecules for that target. A meaningful fraction of all drug development funding is directed towards this process - and I'm willing to wager that none of the autophagy-directed portion of this established way forward will much move the needle on human longevity over the next few decades. Aiming for a few extra years seems a waste given the vastly greater potential of other lines of research and development.
Hevolution backs $30.7m Series A to advance mitophagy drug
Hevolution Foundation has joined forces with Dolby Family Ventures to invest in Vandria, a company pioneering mitochondrial therapeutics, with a view to expediting the development of a promising drug designed to improve cognitive function. The total Series A financing now stands at $30.7 million, with Hevolution and Dolby Family Ventures joining ND Capital as institutional backers. This funding is set to facilitate the clinical advancement of Vandria's lead compound, VNA-318, a small molecule mitophagy inducer aimed at treating neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other age-related conditions.
The investment speaks to a growing interest in mitophagy - an essential cellular process that involves the selective removal and recycling of damaged mitochondria. Mitochondria are critical for maintaining cellular health, and their dysfunction is increasingly linked to numerous human pathologies, including neurodegenerative diseases, cardiovascular disorders, and cancers.
"This financing will enable us to progress further in clinical development with runway from the Series A to complete the Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) first-in-man Phase 1 study of VNA-318 and to initiate three parallel Phase 1b/2a efficacy studies in 2025, subject to positive progress in the Phase 1 and regulatory approvals."