Rapamycin Research Update: Aging Research and Drug Discovery (ARDD) meeting

Newly published summary from the Aging Research and Drug Discovery (ARDD) meeting in September, 2021.

Longevity pathways

Cellular pathways associated with increased longevity have been extensively studied for many years. Consequently, drugs targeting these pathways have been shown to have a positive effect on lifespan in different model organisms.

Rapamycin is known to increase the lifespan of organisms by acting through mTOR. Linda Partridge, Max Planck Institute for Biology of Ageing, Germany, highlighted the importance of intestinal homeostasis and aging. Their research revealed that short term and early treatment with rapamycin extends lifespan in D. melanogaster as much as chronic rapamycin treatment. The short-term rapamycin treatment induced long-term increase in autophagy, decrease in pathology of fly intestine. Similarly, short term rapamycin treatment in mice caused a reduction in intestinal pathology for up to 6 months after rapamycin treatment (unpublished data). Moreover, there is an unconventional intestine sex-specific TORC1-histone axis which uncovers a new aspect to the improved longevity with rapamycin as shown by Yu-Xuan Lu from Max Planck Institute for Biology of Ageing, Germany. The observed sex differences and possible other unconventional pathways need to be considered prior to rapamycin treatment [6].

and in another section its reported:

The benefits of dietary restriction

Another well-described stressor that has been shown to extend lifespan as well as improve healthspan is dietary restriction (DR). With age there is a decrease in RNA but increase in RNA polymerase II (RNAPII), specifically elongation RNAPII, suggesting lower RNA productivity of RNAPII with age as presented by Jan Hoeijmakers, Erasmus Medical Center Rotterdam, Netherlands. This preferentially affects long genes being suppressed in expression leading to an imbalanced RNA pool. DR compensates for this effect by reducing DNA damage load and alleviating transcription stress (unpublished). Maria Birkisdottir, Erasmus MC, Netherlands, showed that DR but not rapamycin leads to an increased health- and lifespan in ERCC1−/Δ mice. Similarly, DR but not rapamycin prevents the observed degeneration of Purkinje neurons in ERCC1−/Δ mice, indicating that DR and rapamycin differ in their mode of action [21]. Moreover, fasting or a ketogenic diet have been shown by Thomas A. Rando Stanford, USA to cause the muscle stem cells to enter a deep quiescent state mediated through HDAC1 and p53. This causes an increased resilience of aged muscle stem cells [22].

The beneficial effects of DR are lost in late-life interventions, potentially because the induction of mitochondrial function is necessary for the response but declines with age.

and in another presentation:

The potential of senotherapeutics is also emerging within the field of skin aging. The CSO of OneSkin Alessandra Zonari presented their latest findings regarding Peptide 14, identified through a cell-based screening. Treatment of aged skin with Peptide 14 caused a reduction in senescence and inflammatory markers and led to an increase in skin health with higher efficiency than rapamycin treatment [38].

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