Building a Better Spermadine to Improve Mitophagy
Researchers here report on their efforts to improve on the ability of spermadine to modestly slow aging in short-lived species, producing new derived molecules with larger effects on the cellular maintenance process of mitophagy. Mitophagy clears damaged and worn mitochondria, and is known to decline in effectiveness with age. A range of approaches that somewhat improve mitochondrial function, including mitochondrially targeted antioxidants such as mitoQ and compounds that raise NAD+ levels such as nicotinamide riboside, may produce their effects via boosted mitophagy.
The related publicity materials for this research note that the academic program has spun out into a new startup, but to my eyes this work is unlikely to result in anything that will greatly move the needle on health and life span in humans. This part of the field, in which upregulation of cellular maintenance processes modestly slows aging in short lived species, has consistently failed to produce anywhere near the same gains in long-lived species. Spermadine is in this category, even given the attempts to produce decent human data for its effects in our species, and a moderately better version of spermadine will most likely still be in this category.
Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer's and Parkinson's diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population.
Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of structurally related compounds. A prototypic member, 1,8-diaminooctane (VL-004), exceeds Spd in its ability to induce mitophagy and protect against oxidative stress. VL-004 activity is mediated by canonical aging genes and promotes lifespan and healthspan in C. elegans. Moreover, it enhances mitophagy and protects against oxidative injury in rodent and human cells. Initial structural characterization suggests simple rules for the design of compounds with improved bioactivity, opening the way for a new generation of agents with a potential to promote healthy aging.