This isn’t exactly news, but it’s news to me: Rapamycin has an orally administered derivative, Everolimus, already in use as an anti-cancer and anti-rejection drug. (The two compounds are almost identical; Everolimus has one additional hydroxyethyl group on the protuberant cyclohexane ring, and apparently that’s enough to make the unwieldy rapamycin molecule orally bioavailable.)

This might be good news if it turns out that the longevity-enhancing qualities of rapamycin end up generalizing to humans: If you need to maintain constant levels of a chronically administered drug, t’s way easier to use timed-release oral capsules than injections. Also, as millions of diabetics will tell you, it’s just nice not to have to shoot up.

But the drug itself might be bad news, especially if it is taken over long periods of time: mTOR, the target of rapamycin, appears to be necessary for reconsolidation of long-term memory in mammals; inhibition of mTOR is efficacious enough at blocking fear memories that it’s discussed as a strategy for treating PTSD. The role of mTOR in memory appears to be general, i.e., in memories other than fearful ones, and it is evolutionarily ancient: TOR is important for long-term potentiation in the sea slug Aplysia, beloved model of scholars of learning and memory.

So, as I’ve commented before, I have this fear that rapamycin (or a derivative) will turn out to be a bona fide longevity enhancement drug, but one whose chronic use erodes long-term memory, which does defeat the purpose to some extent.

Then again, blood-brain barrier is an issue here: even though Everolimus can survive the stomach and pass through the gut into the blood, that doesn’t mean it will make it into the brain efficiently. Then again again, if the drug has a long half-life once it’s inside the brain, it might still accumulate there if one had to take it every day for the rest of one’s life.

On the happy side, if you find this possibility traumatic, the rapamycin will take care of that for you.

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We know that exercise is good for us, and increasingly we’re understanding how it works at the molecular and cellular level: Physical activity boosts levels of heat shock proteins, which help cells resist stress; it also improves mitochondrial function in a manner reminiscent of calorie restriction (CR). Our knowledge is sophisticated enough that we can identify and develop small-molecule exercise mimetics and drugs that improve exercise tolerance.

Overall, then, exercise and its molecular/cellular consequences are consistent with longevity assurance pathways and life extension interventions. However, there are complications emerging.

One of the results of exercise is increased activity of anabolic pathways, especially in muscle. Building up tissues require new protein synthesis, and new protein synthesis requires activity of the TOR pathway. TOR is increasingly thought to be a pro-aging or gerontogenic pathway: rapamycin, a drug that inhibits TOR, blocks senescence and extends lifespan in mice (we already knew that TOR inhibition increased longevity in worms and yeast).

Until recently, we’d believed that exercise modulated TOR in the “right” direction for longevity assurance (i.e., down). For instance, AMPK, a target of exercise mimetics, appears to downregulate TOR signaling.

But it would appear that the above result, obtained using exercise mimetics, may not be generally applicable to all exercise — in particular, it does not extend to a specific regimen of exercise designed to stimulate anabolism and muscle growth. In blood flow restriction (BFR) exercise, resistance training is combined with pressure cuffs that significantly decrease blood flow to the exercising muscle; it increases protein synthesis in muscle cells and activates the TOR pathway. Now, Fry et al. have shown that in older men (who don’t increase muscle mass in response to ordinary resistance training), BFR activates TOR.

Superficially, this would seem to represent a contradiction: a lifespan-extending intervention (exercise) activates a lifespan-shortening biochemical signaling pathway (TOR). How might this seeming paradox be resolved?

  • TOR activity in the muscle might be irrelevant to lifespan control. Testing this hypothesis is a special case of a broader question, which is the determination of the key tissues responsible for the lifespan extension by rapamycin. This will probably require tissue-specific conditional knockdowns of either TOR or downstream pathways (e.g., S6K), and will take a while.
  • Not all exercise is lifespan-extending. Perhaps exercise regimens specifically optimized to stimulate anabolism might be gerontogenic, while those that create acute stress and activate hormetic pathways might extend lifespan.

It’s also worth mentioning that BFR exercise may be uniquely bad vis-a-vis longevity control. In worms, one of the targets of TOR is HIF-1, the hypoxia inducible factor. HIF-1 is a gerontogene: knocking it down extends longevity, so its wildtype function must shorten lifespan. I wonder whether the blood flow restriction in BFR exercise might create low-grade hypoxia in the muscle tissue, inducing HIF-1 activity and incurring some gerontogenic effect. It certainly wouldn’t be the first time that an intervention that helped older men increase muscle mass ended up being bad for them in the long run (e.g., hGH).

ResearchBlogging.orgFry, C., Glynn, E., Drummond, M., Timmerman, K., Fujita, S., Abe, T., Dhanani, S., Volpi, E., & Rasmussen, B. (2010). Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men Journal of Applied Physiology DOI: 10.1152/japplphysiol.01266.2009

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TOR (target of rapamycin) integrates nutrient and energy signals in eukaryotic cells to regulate growth and cell size, and has been linked to aging in various model systems, including yeast.

Yeast is an important model system for biogerontology in general and for the study of telomere biology in particular: yeast cells grow quickly, and its genome can be manipulated with relative ease, alllowing the study of knock in/out strains. The yeast protein Cdc13p (homologous to the human protein Pot1) binds single-stranded telomeric repeats, maintaining genomic integrity and suppressing the activation of Mec1p (the yeast homologue of human ATR, which is involved in the DNA-damage response pathway). Qi et al. have previously demonstrated that inactivation of Cd13p using a temperature-sensitive mutant results in deprotection of telomeres, activation of Mec1p and either senescence or apoptosis (depending on the cellular context). These same authors have continued their studies and now report that TOR plays a pivotal role in the apoptosis that results from deprotected yeast telomeres:

TOR Regulates Cell Death Induced by Telomere Dysfunction in Budding Yeast

Telomere dysfunction is known to induce growth arrest (senescence) and cell death. However, the regulation of the senescence-death process is poorly understood. Here using a yeast dysfunctional telomere model cdc13-1, which carries a temperature sensitive-mutant telomere binding protein Cdc13p, we demonstrate that inhibition of TOR (Target of Rapamycin), a central regulator of nutrient pathways for cell growth, prevents cell death, but not growth arrest, induced by inactivation of Cdc13-1p. This function of TOR is novel and separable from its G1 inhibition function, and not associated with alterations in the telomere length, the amount of G-tails, and the telomere position effect (TPE) in cdc13-1 cells. Furthermore, antioxidants were also shown to prevent cell death initiated by inactivation of cdc13-1. Moreover, inhibition of TOR was also shown to prevent cell death induced by inactivation of telomerase in an est1 mutant. Interestingly, rapamycin did not prevent cell death induced by DNA damaging agents such as etoposide and UV. In the aggregate, our results suggest that the TOR signaling pathway is specifically involved in the regulation of cell death initiated by telomere dysfunction.

The authors began by inactivating Cdc13p to leave the single stranded telomeric overhang permanently unprotected. This resulted in growth arrest and cell death characterized by increased ROS production, increased phosphatidylserine flipping, and caspase activation. However, treatment with rapamycin (which inhibits TOR, and which has been much discussed lately as a possible anti-aging therapeutic) significantly attenuated these effects; cell survival was increased 100-fold and the aforementioned markers of cell death were effectively inhibited.

As Cdc13p binds to telomeres in S-phase, and TOR inhibition delays the G1/S transition, the authors reasoned that the observed protective effects of rapamycin may simply reflect its effect on the cell cycle — i.e., cells do not reach S-phase, and so do not require Cdc13p. As rapamycin did not result in G1 accumulation, however, the authors concluded that the protective effect of rapamycin is unrelated to the delay in the cell cycle.

They next asked whether rapamycin affected the state of the telomeres, by examining the number of telomeric G-tails, telomere length, and the telomere-position effect (TPE; the phenomenon whereby telomere status influences gene expression in sub-telomeric regions). All three measures remained unchanged upon treatment with rapamycin, suggesting that the effect is mediated downstream of telomeric status.

Cell death can also be triggered by mechanisms that are independent of telomere dysfunction. Exposure to either UV or etoposide (a topoisomerase-II poison) induced an apoptotic response that is not rescued by rapamycin treatment, supporting the authors’ hypothesis that the drug specifically prevents telomere-initiated cell death. Inactivation of Cdc13p resulted in elevated ROS, which is abolished by rapamycin (and also by the antioxidants vitamin C and NAC), raising the possibility that rapamycin prevents telomere-initiated cell death via an antioxidant mechanism was raised.

Inhibition of TOR is known to up-regulate Sod2p, but deletion of Sod2p did not affect the protective effect of rapamycin. However, rapamycin treatment was shown to reduce mitochondiral ROS production and increase mitochondiral mass, pointing to regulation of mitochondrial function as the mechanism through which rapamycin prevents cell death. The implied model is that treatment with rapamycin improves mitochondrial bioenergetics, thus reducing the generation of ROS, which are known to impact of telomere dynamics. To provide additional support for this model, the final experiment involved inactivation of Est1p (an essential subunit of telomerase). As with Cdc13p inactivation, rapamycin treatment suppressed the elevated PS flipping and ROS production.

Taken together, the findings support the hypothesis that “the TOR signaling pathway is specifically involved in the regulation of cell death initiated by telomere dysfunction”.

I have often wondered just how telomere biology in yeast relates to telomere dynamics in higher organisms. In particular, S. cerevisiae (used in the present study) is quite different from other organisms in terms of telomere sequences and telomerase activity. A minor point perhaps, but important to note.


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