Lifelong benefits following brief exposure to Rapamycin - LTF Literature Highlight Series

We, at the Longevity Tech Fund closely follow the literature and we plan to provide a summary and analysis of any new and exciting publication that makes waves. This is especially important for us as we move towards our fund two and get ready to make investments in this exciting field of science which has the potential to impact human health.

This week we wish to highlight the recently published Nature article from Juricic, P. et.al  titled “Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy”.

A wide array of gero-protective drugs have been identified since it first became clear that pharmacological intervention could alter the trajectory of organismal lifespans in the late 90’s and early 2000’s. Included among these drugs are sirtuin stimulating agents, NAD+ precursors, calorie restriction mimetics, autophagy inducers, senolytics and several key metabolites. While each of these classes of drugs address different aspects of the aging organism such as genomic instability, mitochondrial dysfunction, altered nutrient sensing, proteostasis, and senescent cells, they have all been found in one way or another to extend the healthy trajectory of an organism's life. One drug in particular, Rapamycin, works by inhibiting mTOR signaling, suppressing pathways of cell growth and conversely upregulating autophagy. The drug was originally discovered as a natural product produced in bacteria from the pacific island of Rapa Nui (Easter Island) and was used as an antifungal agent. Due to it’s mTOR mechanism the drug was later repurposed as an anti-proliferative agent to fight cancer. 

Academic research conducted decades after it’s discovery uncovered that In lower organisms such as flies and worms, rapamycin markedly expanded lifespan multiple-fold, while in mice, reports of life extension ranged between 10-60% added lifespan depending on dosing regimen and age of administration. As such, multiple attempts have been made to commercialize this class of drugs as therapeutic agents against aging associated disease. For example, just this year, Janssen pharmaceuticals acquired Anakuria therapeutics, a company advancing rapamycin analogues against autosomal dominant polycystic kidney disease, or ADPKD. Likewise, in 2020, the first participatory human clinical trials (PEARL and REACH) were approved to uncover whether rapamycin could help reduce clinical measures of aging and cognitive decline in elderly individuals. 

This drug, and derivatives of it (also known as rapalogs), are not without side-effects. Chronic use and larger doses are known to lead to immunosuppression, a use case for which these drugs gained FDA approval. Furthermore, metabolic dysfunctions such as hyperglycemia and dyslipidemia have been reported in patients receiving these types of drugs. As such, the field has been actively pursuing alternative strategies, either through dosing, administration, or medicinal chemistry to try to optimize the use of rapalogs for the purpose of lengthening healthy aging trajectories in the general population. 

This recent publication from the Max Planck institute for Biology of Ageing in Cologne Germany, highlighted the possibility of utilizing a one-time, brief dose of Rapamycin early in adulthood that could provide long lasting benefits in late life without the detrimental effects associated with chronic exposure. The authors found that when young adult fruit flies were given Rapamycin for two weeks, the drug provided gero-protective effects in the gut which translated to longer lives like what would be expected with chronic administration. Importantly, this effect of life extension was most pronounced either when administered chronically or when briefly administered at the earliest stage of life at 1-30 days. If brief administration was initiated anywhere between 15-45 days of life, the flies experienced only modest increases in median lifespan. However, if rapamycin was administered later in life, between 60-100 days, the flies experienced no increases in lifespan. These results are consistent with previous reports in mice suggesting that exposure to rapamycin earlier in life confers more benefits to overall health and longevity compared to administration in late life. 

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The authors found that this phenotype was directly linked to improvements in the intestinal stem cells and enterocytes particularly as it related to their rates of autophagy. The authors referred to these improvements, which manifested as a more robust gut barrier integrity later in life, as ‘rapamycin memory’ that persisted long after the drug was cleared from the system. They were able to trace this memory to a lifelong upregulation of lysozymes and lysosomal mannosidases that aided in the autophagic process and were directly modulated by rapamycin exposure. Importantly, the authors replicated their findings in mice by administering rapamycin for 3 months starting at 3 months of age and finding that gut barrier integrity was maintained in middle age. 

These findings are exciting as they suggest that a readily available aging intervention can be used briefly, once in life and confer benefits that persist decades later. This dosing paradigm would be entirely unique as no other drug is prescribed in this manner and could completely dissolve any concerns in the healthcare community about unintended side effects of chronic use. Likewise, such a dosing scheme would greatly simplify clinical trial design and potentially expedite drug approval processes. Clearly, however, it seems that such an approach would mainly benefit those individuals that are young, as older individuals don’t seem to benefit from brief rapamycin administration. Importantly, although the authors confirmed their findings of brief rapamycin exposure and long-lasting gut health in mice, they didn’t report potential benefits of brief exposure in other tissue types and the mouse’s overall lifespan and health. It may be that their dosing length and timepoint is not optimal to benefit the organism at large. A more thorough and lifelong analysis will be required to provide better insights into the translatability of these findings as it has long been known, especially as it relates to aging-interventions, that lifespan extension in invertebrates like flies and worms doesn’t translate perfectly to larger mammals like non-human primates. 

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