Even with calorie restriction, rapamycin slows muscle aging

A new research paper came out today with more good news on how rapamycin can slow aging. This time the focus of the research is rapamycin’s effect on muscle aging, and how it could complement caloric restriction, another well-proven anti-aging strategy.

The issue of rapamycin impact on aging muscle has been of significant interest in our discussion forum and there is a good, long discussion thread on the science and personal experiences of people using rapamycin, and its positive impact on muscle. And there is another thread here on rapamycin use with muscle training, etc. (with photos of results).

This new study seems to suggest that fasting, in combination with rapamycin, might provide even more positive impact in terms of slowing the aging of our muscles. This study seems to confirm some of what we (the rapamycin users here) are seeing in our own lives.

Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging.

Full paper here: Distinct and Additive Effects of Calorie Restriction and Rapamycin in Aging Skeletal Muscle

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This is an amazing study, thanks for sharing! I don’t think I’ve seen a CR/Rapamycin dual intervention mice study prior.

Further insight into the disentangling of longevity interventions NOT being all about mTOR1, just as muscle build with resistance exercise is not blunted by Rapamycin or mTOR inhibition.

It’s quite clear that Rapamycin is not a CR mimetic, and longevity interventions have complex, still yet undiscovered pathways (e.g. the recent paper out of the Miller ITP lab showing Cap-independent translation as a common, but separate non-mTOR1 pathway to longevity: Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol - PubMed)

And I think this and others are great finds…there are yet undiscovered additional therapeutic pathways to longevity.

I wonder if this lab is doing/planning a true longevity study on the dual CR/Rapamycin intervention?

But how many of us are going to do true CR (35% in the study), and loose 26%+ body weight, irrespective of the scientific nuance of “cellular” muscle function preservation? Sure, the study highlights some beneficial age preserved muscle functions by normalizing them to the residual body mass of the CR mice, masking the relative loss, but the absolute loss is large. From the paper “Adaptations to calorie restriction favor whole-body muscle function but DO NOT prevent an age-related decline” Translating to humans, the risk of frailty and injury in old age from such low skeletal mass? Do I really want a smaller heart, liver, kidney…brain?? I still want to lift an apple when I’m old, not just a grain of rice!

I read another recent paper recently which also showed at CR and Rapamycin promote longevity vs distinct pathways: Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice - PubMed (a unique Progeria mouse model)

“Together, this indicates that inhibition of mTOR signaling, including reduced phosphorylation of ribosomal protein S6, fails to improve life span, and does not mediate the beneficial effects of DR in these mice. Even less than 25% of the life span extension exerted by 30% DR would have been easily picked up in our model, stressing the disparity between rapamycin and DR to delay the aging features accelerated in progeroid DNA repair mutants. This points to fundamental differences in the way mTORC1 signaling and DR act, consistent with recent findings of dissimilar effects on multiple pathways and molecular processes, by DR and rapamycin in WT mice, indicating that they extend life span through different mechanisms, again questioning the extent to which rapamycin can be regarded as DR mimetic. Rapamycin may extend survival mainly via acting only on a narrow
subset of aging traits, in particular altered immune function and suppression of cancer. This indicates that rapamycin and DR largely work via different mechanisms, DR in part, a “survival response” via attenuating the GH-axis (e.g. GH, IGF1, TH). Hence, an important anti-aging effect of DR may be triggering the protective “survival response”, which includes boosting anti-oxidant defenses and metabolic redesign thereby reducing the DNA damage load, consistent with the alleviation of genome-wide transcription stress by DR”

One of the reasons I practice ketogenic/one meal a day fasting is to try and induce, at some level, some of the gene expression of CR, without doing full CR (the main reason is ketone generation, a longevity signal metabolite in its own right).

The lower protein, mTOR, insulin, glucose, IGF-1 AUC and higher ghrelin signalling…my body definitely “thinks” I am starving myself by not eating for 24 hrs, but yet I’ve been weight stable for 4 years after rapidly losing about 50 lbs. My thyroid markers indicate a “starving” signal from my brain to periphery, since my free T3 is way down from normal (evolutionary signal). My body is being tricked to rev slower, as it thinks I’m in calorie deficit, when I clearly am not. I am more sensitive to shivering in the cold (typical side effect of keto), including my extremities. Extended multi-day fasting, something many people to for the beneficial hormetic stressor signals (“CR bursts”) but they start to creep into lean muscle mass loss (something VERY hard to build and rebuild), and yo yo re-feeding to reset to baseline weight. Some might find this an acceptable/practical pathway to some level of CR signal. Clearly from this paper, there is merit to doing some form of “calorie reduction mimetic signal” independent of my taking Rapamycin. It clearly does not impact aging muscle function per se. And I am blunting aging related sarcopenia not with more protein, not pharmacologically, but with resistance exercise.

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Its Interesting to note that:

In conclusion, CR-induced reduction of content/ phosphorylation levels of key proteins in mTOR signaling and the UPP occurred in the middle-aged rats but not younger rats. The age-dependent effects of CR on mTOR signaling and the UPP indirectly explained the age-related effects of CR on muscle mass of animals.

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Yes, interesting nuance. Well, you started the rabbit hole…

From the paper, other pathways remain unexplored, but inflammation rationalized to explain the difference in old aged vs young:

“Although UPP is one of the key pathways that degrade proteins, other pathways such as calpain, apoptosis, and autophagy-lysosome machinery also involve in cellular protein degradation. The role of other muscle degradation systems in the CR-induced preservation of muscle mass of older animals needs further studies. The underlying mechanism to explain the responses in mTOR signaling and UPP with CR and age is likely related to the cellular environment. The inflammatory
profile in skeletal muscles increases with aging. Thus, our finding of the concurrent upregulation of both anabolic and catabolic signaling pathways in aging muscles is likely a response to the inflammatory environment present in skeletal muscles of older animals. Because CR decreases inflammation, its impact is significant in the older animals compared to younger animals. Nevertheless, CR has potential adverse effects for certain biological systems and animals with specific genetic backgrounds (Contreras et al. 2018). For example, healthy individuals with long-term CR had lower leukocyte count which may compromise the defence function of their immune system compared to age-matched individuals who maintained a Western diet”

Why didn’t they measure INFLAMMATION markers in their mice??

From the Contreras paper, I extracted the human CR metrics:

The immune metrics for the CR group are hovering at the LL values using the lab ranges where I am. So they aren’t significantly BELOW.

“From these data, we conclude that CR drives a reduction in total leukocyte cellularity, either by sequestration in tissues or a contraction/elimination during periods of reduced calories”

We know from the cancer/Sirolimus/GFJ paper (high dosing, cancer patients), Lymphopenia was a major adverse event, but this cohort of CR humans, those immune markers aren’t below lower limit.

Back to the CR mice:

“In middle-aged 10- month-old mice, we found that during periods of caloric restriction, the absolute number of lymphocytes within the blood, inguinal and brachial lymph nodes, and spleen is reduced in comparison to AL fed counterparts. By contrast, the bone marrow of CR animals appeared to be a site of influx, or a safe haven for B, NK, and T cells, the numbers of which were at least intact, if not elevated in bone marrow. An obvious question of interest in this model relates to the functional consequences of CR-induced lymphopenia on immune defense. We and others have shown that systemic sepsis (Sun et al. 2001), epithelial and cutaneous infections all produce substantially higher mortality in old mice on lifelong CR. Less is known about vulnerability of mid-life animals in the course of CR induction, or for that matter, animals that are not held within specific pathogen free environments”

And in case you’re wondering about changes in spleen and thymus size in CR mice:


Some reference all-cause mortality (THE human metric to talk about in any longevity studies) and association with BMI:

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(18)30288-2/fulltext

And for centenarians (average BM: 21.8)

And how critically important is muscle and sarcopenia avoidance for longevity:

“Conclusions: Our findings show that physical function impairment, but not multimorbidity, is predictive of mortality in older community-dwellers with sarcopaenia. Hence, in sarcopaenic older persons, interventions against functional decline may be more effective at preventing or postponing negative health outcomes than those targeting multimorbidity.”

"Shockingly, the ill-effects of sarcopenia were virtually independent of whether or not subjects also had 2 or more conditions/diseases typical of old age, including: “obesity, coronary heart disease, cerebrovascular disease, congestive heart failure, peripheral artery disease, hypertension, lung disease (chronic obstructive pulmonary disease, emphysema or asthma), osteoarthritis, diabetes, dementia (Alzheimer’s disease and other forms of dementia), Parkinson’s disease, renal failure and cancer (non-melanoma skin cancer excluded).”

In other words, have sarcopenia, die early, regardless of what other ailments you do or do not have.

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35% or even 50% caloric restriction is quite doable with proper nutrition. But the “gains” will be related to how early in life it started whether its 20s 40s etc. Yes they will probably have less muscle mass, but it wont be that much difference functionally.

I think people often confuse the performance decline or even morbidity to exact aging when in truth actually often things that protect against death (in older age) speed up aging. This paradoxical concept is very important in truly understanding how to target aging.

@ Potionology

Most certainly doable, although it seems no one (extreme few) are proactively doing it, even though the literature is very strong on the chronological longevity benefits, and costs…ZERO.

Straw poll…anyone on this forum doing CR or know anyone doing CR?

I’d have to loose 20 lbs to get to the centenarian BMI average of 21.8. I’d have to give up a lot of hard earned skeletal mass/muscle to get down to this lower weight (low body fat currently). I feel super resilient where I am at 57.

I’d still be functional no doubt at the 21.8 BMI, but would I want to have such lower reserve as I age? My dad, since passed, I watched him steadily decline in skeletal muscle/strength, probably was low BMI last years. He had an accidental fall, bone fractures, it was the trigger for his steep demise. I want to have more buffer/resiliency, but would I be sacrificing absolute longevity? Cause vs. effect, or just an association? Is it genetics, or instead metabolic marker optimization?

All the old people I know (85+, sample size 9), NONE are low BMI, certainly no where near 21.8. The longest lived, approaching 95, an independent living, non frail muscular man. I’ve known him my whole life, and he was uniquely muscular as early as I can remember as a kid (general labourer, not exercise intervention). He could still probably beat me in an arm wrestle. My father in law, turning 88 this week, is a robust, HIGH BMI man, yet very functionally strong, nowhere near frail.

Peter Attia (prominent internet longevity focused doc) recently said bicep muscle diameter is as good as any predicting longevity.

It’s well accepted now that long lived individuals, they “escape” morbidities due to unique genetic signatures. They have very efficient DNA repair genes. I don’t have any exceptional longevity on my family side. It will require herculean epigenetic interventions to escape to centenarian.

“The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging”

What is the Optimal Body Mass Index Range for Older Adults? February 2022

“Conclusion: Older adults with BMI <25 and >35 kg/m2 were at a higher risk of a decrease in
functional capacity, and experienced gait and balance problems, fall risk, decrease in muscle strength, and malnutrition. Data from this study suggest that the optimum range of BMI levels for older adults is 31–32 and 27–28 kg/m2 for female and male, respectively”

“Body mass index (BMI) values of non-frail participants were found significantly higher than mildly, moderately, and severely frail participants. It was observed that there was a statistically significant and negative correlation between the participants’ frailty scores and muscle mass. A negative correlation between hand grip strength and frailty scores was also observed”

Here’s a very interesting one, given the issues of Neutrophil/Lymphocyte risk of Rapamycin:

Association Between Neutrophil–Lymphocyte Ratio (NLR) and Frailty: The Chinese Longitudinal Healthy Longevity Survey

“Among community-dwelling older adults, higher NLR levels were found to be associated with increased odds of prevalent and incident frailty”

If one is to proceed down this path proactively, most critical would be to ensure you add resistance exercise to achieve high muscle functionality/power to make oneself super strong for the muscle mass you have. You cannot risk sarcopenia (certainly preventing longevity) and frailty. I am not aware of any research showing reduced longevity with higher muscle functionality. And stay away from any falls, there will be little fat/muscle to protect you!

Yes - longer term caloric restriction is really hard… I’ve tried it in the past for a year - was a member of the CR society, we were in a small group of people buying ready made meals (made by the wife of one of the guys) of specific caloric nutritional content from Roy Walford’s books… lost 20 or 30 lbs , was always cold and hungry… gave up after a year. Its hard. Some people can do it, a small percent of the population, but not too many.

At the same time - I do find it very easy to maintain a lower weight (BMI Approx. 23, slowly trending downwards), with rapamycin, and an SGLT2 inhibitor. I think that with 17 Alpha estradiol that we could all get to that Centenarian optimal BMI, while also maintaining most of our muscle mass.

Yeah, I figured it was very hard indeed. But kudos for even trying!

I am not convinced it’s a muscle mass/BMI thing per se, but having an optimal biomarker longevity “signal” and certainly being very resilient/functionally strong in old age.

Unless one is blessed genetically, perhaps modern interventions can help the rest of us “escape” as you suggest.

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As Potionoloogy says above, in the mice research, CR must be instigated early to be effective. I think you’re right, avoiding sarcopenia should be high priority. Indeed this was the primary ‘selling point’ of Rapamycin for me personally (not the potential longevity benefits) as I want to be competitive as a Masters athlete.

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My last properly measured BMI was 21.7 (with a fat % of 9.1) and my weight has remained stable for a couple of years now. Does that mean I practice CR?
I never measured the calories I consume. I feel I have to eat a lot in my 8 hour feeding window just to maintain my existing weight and BMI. I’m not sure I could get away with eating any less than what I already consume - any thoughts on this?

Whilst writing, MAC, as you practice low protein keto like diet, could you please give us an idea of what you would typically eat?

If that’s been your long baseline metabolic rate/calories/weight…technically, you’re not practicing CR I don’t think. I believe one must “induce” a chronic calorific deficit state to cause change in the epigenetic signal. You need to remodel gene expression from baseline.

I practice a plant fat based keto. My typical single meal of the day (at dinner), immediately after exercise:

  • Whole avocado
  • Couple Tablespoons EVOO (extra virgin olive oil)
  • Large handful macadamia, walnuts, pecans
  • Couple squares zero sugar dark chocolate
  • Tablespoon Almond Butter
  • 20-25 grams aged cheddar (ok a bit of animal fat)
  • Wild, very low fat animal protein (200g): Sockeye salmon*, wild shrimp, grass fed lean beef, scallops, eggs, crab.
  • As much leafy green/dark colored veggies as I can stuff myself with (kale, asparagus, broccoli, rapini, peppers, mushrooms, spinach, swiss chard, etc). Nothing below ground/carby.
  • No fruit except some blackberries/blueberries
  • I test my mercury often, I don’t eat any large fish other than the Sockeye…they are LOADED with mercury. The wild pacific sockeye is ok for mercury.

I don’t count calories, I go for macro percentages to ensure I’m in ketosis (I stopped doing blood ketone pricks after adaptation), satiation, and the weight scale.

Look at your plate and try to replace/add higher energy/nutrient foods to get the calories/nutrients/satiation.

“Physical inactivity or a decreased physical activity level is a part of the underlying mechanisms of sarcopenia and therefore physical activity can be seen as an important factor to reverse or modify the development of this condition.” This and many similar statements will be found when searching for sarcopenia studies.

My belief is lack of regular exercise among older adults is the primary cause of sarcopenia. Taking up exercise when you are old will make you stronger but will not increase muscle mass significantly. Unfortunately, I have not been able to find a study that looks at people who have consistently exercised for decades to those who only took up exercise later in life.

I personally have not had any loss of muscle mass (I am 81) but I have had regular exercise exposure of various sorts for much of my life except for a few periods when for various reasons it was not practical.

I have had really good results from time-restricted eating. Currently, I do 18/6 or 19/5. My diet is varied and I have no particular plan. I would describe my diet as basically South Beach, with moderate protein and moderate carbs. When eating with friends I never say “Oh, I can’t eat that!” At holiday dinners such as Thanksgiving, I will eat pie and ice cream. I eat 70% dark chocolate daily.

My current BMI is 22 and I have to work to eat enough to keep it there. I previously posted my Levine Phenotypic age calculator results that show an approximate 15 year younger phenotypic age. (My smart scale says I am 22 years younger. LOL) I just completed my second round of 100, 1mg tablets of rapamycin and had blood work taken today at Quest Diagnostics and will post the results when I get them.

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@desertshores

This is when he was 81, 9 yrs ago:

I don’t know of a fundamental physiological reason why you cannot induce hypertrophy/hyperplasia or other muscle build pathway, in muscle, if sufficiently mechanically loaded. You just need to push the envelope in load/volume to overcome.

The % increase is lower for older people, but no reason one cannot build significant muscle mass in older persons.

Conclusions: Aging can attenuate the hypertrophic response of muscle groups to resistance training, when the training load is proportional to baseline strength. However, aging does not impair training-induced increases in specific tension. A reduced hypertrophic response to weight lifting
in older people therefore should not be used to argue against strength training in old age"

Influence of Resistance Exercise on Lean Body Mass in Aging Adults: A Meta-Analysis

“Conclusions—RE is effective for eliciting gains in lean body mass among aging adults,
particularly with higher volume programs”

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I think what I should have said, am I technically practicing CR since my diet revamp over 2 years ago, since all the rubbish and sugar is now gone - given I’m reasonably close to what you are eating on 5-6 days a week (albeit I’m probably consuming a bit more than you and in two sittings but definitely must be less than the calories that used to go in my mouth).
Anyway, thanks for sharing, that’s much appreciated.