Most of the approaches shown to slow aging in laboratory species influence the same underlying mechanisms, meaning the regulation of cell maintenance processes that are activated in response to stresses such as heat, cold, lack of nutrients, and so forth. Arguably the most well studied of these processes is autophagy, a recycling of damaged and excess structures in the cell. This response to stress is fundamental to the evolutionary success of multicellular life, and has existed in more or less its current form for so long that its tendrils sprawl throughout every part of the complex map of cellular biochemistry. Any unbiased search for ways to slow aging will primarily, arguably near entirely, find ways to mimic portions of the response to stress - and researchers have been conducting these searches for decades.
Given a diverse set of apparently unrelated interventions that all turn out to slow aging by affecting different portions of the regulatory system governing stress responses, the next step is to join these dots together. Research of the sort reported in today's open access paper has become commonplace. Here, and in many other cases, researchers find a link between intervention A (in this case rapamycin) and intervention B (in this case spermadine), which leads to a better understand of how the two intervention fit into the regulatory systems governing cell maintenance activities, autophagy in particular.
A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity
Polyamines, including putrescine, spermidine, and spermine, as well as their precursors and regulatory enzymes, are highly conserved across species. Our previous work has highlighted the multifaceted consequences of spermidine supplementation, which exerts cardioprotective and neuroprotective effects, stimulates autophagy and mitochondrial function, and extends lifespan in a variety of laboratory models. These findings are particularly salient given that polyamine metabolism, predominantly regulated by the pacemaker enzyme ODC1 (ornithine decarboxylase 1), is a critical driver of cellular growth. The concordant activity of polyamines, stimulation of cell growth and induction of autophagy, differs from the discordant action of MTOR (mechanistic target of rapamycin kinase), which stimulates cell growth but represses autophagy.
Rapamycin, a potent and selective inhibitor of MTOR, has long been recognized for its ability to extend longevity across species, including yeast and worms. Our recent data demonstrate that rapamycin treatment in yeast is accompanied by a concomitant increase in endogenous spermidine levels. Notably, the inhibition of endogenous spermidine synthesis significantly attenuates the autophagy-inducing and longevity-promoting effects of rapamycin in yeast, human cell lines, and worms, underscoring the essential role of polyamine metabolism in these processes. Accordingly, our study provides further compelling evidence that the pro-autophagic and lifespan-extending effects of dietary restriction and intermittent fasting - physiological triggers that shut down TOR signaling - are largely dependent on functional endogenous polyamine metabolism.
Acute fasting is associated with an increase in polyamine levels across multiple species and tissues, supporting our hypothesis that this rise in polyamines is necessary to trigger the autophagic cascade. Moreover, genetic perturbation of MTOR activity in transgenic mice further corroborates our findings, as changes in spermidine levels align with expected autophagic outcomes. Notably, our previous work has shown that spermidine can effectively counteract the downstream effects of hyperactive insulin-IGF1 signaling during cardiac aging in mice. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.
View the full article at FightAging
