Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice

Blagosklonny, Mikhail V.

doi:10.18632/aging.204354

Cited by 7 publications

(6 citation statements)

References 70 publications

(99 reference statements)

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“…Also mentioned were paradoxical differences between relationships of adult body size to longevity in comparisons among vs. within species. The picture that emerges from the available evidence is consistent with the concept of developmental programming of aging which is supported by much experimental evidence as well as theoretical considerations [ 96 , 100 - 104 ]. In particular, faster early growth and greater body weight of juveniles have been related to higher morbidity and mortality in studies of mice [ 105 ], dogs [ 106 ], and humans [ 107 , 108 ].…”

Section: Pace-of-life and Aging Relationships Of Early Growth And Ear...supporting

confidence: 67%

Relationships among Development, Growth, Body Size, Reproduction, Aging, and Longevity – Trade-Offs and Pace-Of-Life

Yuan,

Hascup,

Hascup

et al. 2023

Biochemistry Moscow

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Relationships of growth, metabolism, reproduction, and body size to the biological process of aging and longevity have been studied for decades and various unifying “theories of aging” have been proposed to account for the observed associations. In general, fast development, early sexual maturation leading to early reproductive effort, as well as production of many offspring, have been linked to shorter lifespans. The relationship of adult body size to longevity includes a remarkable contrast between the positive correlation in comparisons between different species and the negative correlation seen in comparisons of individuals within the same species. We now propose that longevity and presumably also the rate of aging are related to the “pace-of-life.” A slow pace-of-life including slow growth, late sexual maturation, and a small number of offspring, predicts slow aging and long life. The fast pace of life (rapid growth, early sexual maturation, and major reproductive effort) is associated with faster aging and shorter life, presumably due to underlying trade-offs. The proposed relationships between the pace-of-life and longevity apply to both inter- and intra-species comparisons as well as to dietary, genetic, and pharmacological interventions that extend life and to evidence for early life programming of the trajectory of aging. Although available evidence suggests the causality of at least some of these associations, much further work will be needed to verify this interpretation and to identify mechanisms that are responsible.

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Section: Pace-of-life and Aging Relationships Of Early Growth And Ear...supporting

confidence: 67%

Relationships among Development, Growth, Body Size, Reproduction, Aging, and Longevity – Trade-Offs and Pace-Of-Life

Yuan,

Hascup,

Hascup

et al. 2023

Biochemistry Moscow

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“…Studies in model organisms indicate that the timing of administration of rapamycin for longevity-enhancing benefit may be crucial with effects dependent on intervention start and duration 72 . However, our MR estimates represent life-long consequences of perturbing a drug target and so they may not depict the magnitude of a drug intervention’s effect but rather inform us about its presence and direction 73 .…”

Section: Discussionmentioning

confidence: 99%

Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

Sobczyk,

Gaunt

2023

Preprint

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ObjectiveThe mechanistic target of rapamycin (mTOR) pathway plays an integral role in cellular metabolism, growth, and aging. While rapamycin and its analogs inhibit the mTOR pathway, extending lifespan in various organisms, the long-term safety and efficacy of these compounds in humans remain understudied.MethodsUtilizing two mTOR expression QTL instruments derived from the eQTLgen and MetaBrain studies, we sought to explore the potential causal relationship between mTOR expression inhibition in blood and brain cortex (mimicking chronic rapamycin use), and its effects on longevity, cardiometabolic disease, prostate cancer and anthropometric risk factors. Subsequently, we extended the selection of instruments to 47 other members of the mTOR pathway. To complement this Mendelian randomization (MR) evidence, we conducted genetic colocalisation and sampling-based enrichment testing.ResultsOur findings suggest that genetically proxied mTOR inhibition may increase the odds of attaining top 1% longest lifespan in the population (OR=1.24, OR95%CI=1-1.53, p-value=0.048). Moreover, mTOR inhibition significantly reduced body mass index (BMI), basal metabolic rate (BMR), height, and age at menopause, while increasing bone mineral density. Interestingly, there was generally little evidence linking mTOR inhibition to cardiovascular disease incidence, with the exception of weak evidence for a protective effect against heart failure (OR=0.94, OR95%CI=0.89-0.99, p-value=0.039). Chronic mTOR inhibition did not causally affect prostate cancer incidence but increased the risk of developing type 2 diabetes. A higher-than-expected (p-value = 0.05) number of genes in the mTOR pathway were causally associated with BMR.ConclusionsThis study highlights the potential lifespan-extending effects of mTOR inhibition and its significant influence on metabolic risk factors and disease. Members of the mTOR complex, especially mTORC1, play a disproportionate role in influencing BMR and BMI, which provides valuable insight for potential therapeutic target development.

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“…In numerous studies, rapamycin extended lifespan in normal strains and genetically heterogeneous mice and wild mice (see for references [20]). Cancers are the leading cause of death in most mouse strains used for these studies [21,22].…”

Section: Rapamycin Delays Cancer In Normal Micementioning

confidence: 99%

“…There are no pre-cancer cells so early in life, and the treatment with rapamycin is brief. One explanation is that by reprogramming development-driven aging, rapamycin retards aging and therefore delays cancer [20].…”

Section: Rapamycin Slows Aging Thus Delaying Cancer Furthermentioning

confidence: 99%

Cancer prevention with rapamycin

Blagosklonny

2023

Oncotarget

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Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted. www.oncotarget.com in ten or twenty years from now, data will accumulate for retrospective analysis of cancer-prevention with rapamycin in humans.

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Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice

Cited by 7 publications

References 70 publications

Relationships among Development, Growth, Body Size, Reproduction, Aging, and Longevity – Trade-Offs and Pace-Of-Life

Relationships among Development, Growth, Body Size, Reproduction, Aging, and Longevity – Trade-Offs and Pace-Of-Life

Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

Cancer prevention with rapamycin

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