Late Life Rapamycin Treatment Reverses Diastolic Dysfunction in Mice

Inhibitors of mTOR such as rapamycin are increasingly well studied. This class of drug stimulates cellular stress responses, principally autophagy, and thus produces outcomes that are broadly similar to the long-term improvement of health resulting from calorie restriction, exercise, or other demonstrated means of upregulating autophagy. This results in benefits to health, such as those noted in today's open access paper.

It is one thing to demonstrate that a drug improves measures of autophagy known to decline with age, and note that many of the interventions shown to modestly slow aging in laboratory species are characterized by improved autophagy. It is quite another to determine the links between low-level change in cell biochemistry and high level tissue properties. Cellular metabolism is enormously complex, and comparatively little headway has been made towards building broad bridges between (a) specific causative mechanisms of aging, (b) downstream issues with cellular biochemistry such as faltering autophagy, and (c) mechanical, structural, and other properties of tissue and organ function. It remains the case that knowing that a particular intervention works to improve health does not imply knowing how it works to improve health in detail.

Late-life Rapamycin Treatment Enhances Cardiomyocyte Relaxation Kinetics and Reduces Myocardial Stiffness

Diastolic function is controlled by active relaxation of cardiomyocytes and passive stiffness of the myocardium. Cardiomyocyte relaxation is controlled by the interplay of two macromolecular systems: membrane bound Ca2+ handling proteins to send the signal to start and stop contraction, and sarcomeric proteins for force generation and contraction regulation by Ca2+. Passive stiffness of the myocardium is controlled by mechanisms such as extracellular matrix remodeling, titin isoform shift and titin phosphorylation. It has been shown that rapamycin reduces the age-related increase in passive stiffness of the myocardium. The effects of rapamycin on active cardiomyocyte relaxation and the precise molecular mechanisms of rapamycin mediated reduction in passive myocardial stiffness remain unknown. Identifying the mechanisms by which rapamycin improves diastolic function in the aging heart will advance our understanding on its therapeutic potentials in cardiac aging and heart failure with preserved ejection fraction (HFpEF).

To dissect the mechanisms by which rapamycin improves diastolic function in old mice, we examined the effects of rapamycin treatment at the levels of single cardiomyocyte, myofibril, and multicellular cardiac muscle. Compared to young cardiomyocytes, isolated cardiomyocytes from old control mice exhibited prolonged time to 90% relaxation (RT90) and time to 90% Ca2+ transient decay (DT90), indicating slower relaxation kinetics and calcium reuptake with age. Late-life rapamycin treatment for 10 weeks completely normalized RT90 and partially normalized DT90, suggesting improved Ca2+ handling contributes partially to the rapamycin-induced improved cardiomyocyte relaxation.

In addition, rapamycin treatment in old mice enhanced the kinetics of sarcomere shortening and Ca2+ transient increase in old control cardiomyocytes. Myofibrils from old rapamycin-treated mice displayed increased rate of the fast, exponential decay phase of relaxation compared to old controls. The improved myofibrillar kinetics were accompanied by an increase in MyBP-C phosphorylation following rapamycin treatment. We also showed that late-life rapamycin treatment normalized the age-related increase in passive stiffness of demembranated cardiac trabeculae through a mechanism independent of titin isoform shift. In summary, our results showed that rapamycin treatment normalizes the age-related impairments in cardiomyocyte relaxation, which works conjointly with reduced myocardial stiffness to reverse age-related diastolic dysfunction.


Interestingly, a little-known synthetic alkaloid derived from tobacco plant, drug MyMD-1 (isomyosamine) exhibits similar biological activities to mTOR inhibitors rapamycin, everolimus and sirolimus owing to their largely overlapping mechanisms of action. Furthermore, MyMD-1 markedly outperformed rapamycin in a mouse longevity study (see DOI:10.1093/gerona/glac142). MyMD-1 is available orally as capsules. Commercial efforts are currently evaluating the effectiveness of MyMD-1 in Phase II studies for treating sarcopenia/frailty and other early-stage clinical trials are evaluating its use for rheumatoid arthritis (RA), with the potential to expand into other applications. (see: NCT05283486)
It is not in vain that many smokers like Jeanne Calment, Winston Churchill, Christian Mortensen, Emiliano Mercado del Toro, in spite of smoking mortality statistics, lived for a very long time. What was their secret to reverse the harm of tobacco and use its benefits, such as isomyosmin and NAD+ precursors?.

Posted by: Dmitry Dzhagarov at July 15th, 2023 4:45 AM

Jeanne Clement did not start smoking until she was "112". And she probably only smoked for the cameras because she loved the attention it brought her ( and as I have expressed before on this site, I think she was a fraud).

Why the hate for Matt K, he is a researcher not a prescribing doctor?

Posted by: JohnD at July 16th, 2023 11:33 AM
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