Q&A Report: Targeting Biological Aging: A New Paradigm for 21st Century Medicine

M. Kaeberlein: I agree that lifestyle plays an important role in healthy aging, but even people who practice an optimal lifestyle still undergo biological aging and develop chronic disease and disability. I don’t think it’s an either-or situation. I would also encourage you to recognize that lifestyle interventions have side effects very much like drugs do. Consider exercise for example. Anyone who exercises regularly at a moderate or higher level will experience side effects. Those may include muscle soreness, tendonitis, lethargy/fatigue, sprains and broken bones, even death. I don’t think it’s useful to think of pharmacological interventions as either better or worse than other lifestyle interventions. They are just one strategy in our arsenal.

M. Kaeberlein: This is a bit complicated, because nearly all of the intermittent fasting studies in mice are actually caloric restriction. There isn’t much good data showing benefits from isocaloric intermittent fasting in mice and the benefits appear to be much smaller than you get from rapamycin treatment or caloric restriction. At a molecular level, yes, I’d say there are similarities – overlapping but distinct is how I think about it. Among the shared changes are reduced organ size, increased ketogenesis, enhanced autophagy, reduced growth hormone signaling, and – of course – reduced mTOR signaling.

M. Kaeberlein: Any dog can be in the Pack. In order to be eligible for the Foundation, Precision, or TRIAD cohorts we need to know within about a year or so of the dog’s actual age. You will be asked to provide an estimate of the dog’s age and your degree of certainty as part of the Health and Life Experiences (HLES) survey.

M. Kaeberlein: I have taken low dose rapamycin cyclically in the past and likely will again. I don’t make any recommendations on what others should do. I have not experienced any side effects associated with rapamycin personally. The only benefit I attribute to rapamycin was a striking and rapid improvement in adhesive capsulitis or frozen shoulder, which was resolved within a few weeks of starting an 8 week low-dose rapamycin regimen.

M. Kaeberlein: There is preclinical data in both mice and human cells that rapamycin can improve progeria, and I believe there was a clinical trial in combination with farnesyltransferase inhibitors in progeria patients. I don’t know the results of that study.

M. Kaeberlein: Perhaps. I’m aware of one small study aimed at thymic rejuvenation in humans which has been published. The results look encouraging but the study has obvious limitations and needs to be expanded. https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028

M. Kaeberlein: That’s one of the many downstream effects of rapamycin that likely contribute to the various benefits in terms of healthy aging, at least in mice. Teasing out the various mechanisms downstream of mTOR and rapamycin is one of the real challenges in this field right now.

M. Kaeberlein: The current thinking is that rapamycin is produced by certain bacteria to inhibit growth rate of competing eukaryotic cells in their niche. Bacteria do not have an mTOR protein and do not appear to be sensitive to rapamycin.

M. Kaeberlein: There are really too many to list here and they cover a wide range of types of diseases and disorders. In the context of aging, there is good evidence that rapamycin improves age-related declines/pathology in heart, brain, liver, kidney, muscle, reproductive, immune, and oral tissues among others.

M. Kaeberlein: In order to have statistical power to detect a chance in the 3-year time frame, we needed to have larger dogs. You are correct that it’s possible we will miss something, but that is unfortunately the nature of clinical trials and limited resources. You make the best educated guesses you can when it comes to design.

M. Kaeberlein: Yes, although this hasn’t been studied as much as other age-related changes. Here is one study in rats: https://pubmed.ncbi.nlm.nih.gov/26395886/

M. Kaeberlein: This is a tough question to answer. My guess is that for certain types of heart failure, particularly those that involve hypertrophy, there’s a good change it would. What seems to be clear in mice and perhaps in dogs is that the declines in heart function which go along with aging can be reversed by rapamycin treatment. Once it becomes true heart failure, it’s unclear whether the same mechanisms are at play. I know of planned studies in dogs to look specifically at the effects of rapamycin on dilated cardiomyopathy (DCM) and valvular degeneration, but no data that I’m aware of yet. I think DCM in particular is a good bet.

M. Kaeberlein: Intermittent fasting with caloric restriction (nearly all mouse studies are this) has many of the same benefits as rapamycin – I think of them as partially overlapping interventions in terms of molecular mechanisms and phenotypes. Isocaloric IF has not really been studied in any detail in mice, but the existing studies suggest that IF has minimal if any real benefits for lifespan. So isocaloric IF does not recapitulate the effects of rapamycin, at least in mice.

M. Kaeberlein: Rapamycin reverses periodontal disease when started at 20 months of age in mice, so these are pretty old animals. Roughly equivalent to 60–65-year-old people. We haven’t looked in older mice yet, but it’s a good question.

M. Kaeberlein: As far as I know, this hasn’t been carefully examined. Rats on rapamycin show preservation of muscle with aging, but I don’t think the combination has been carefully studied.

M. Kaeberlein: There is data in both mice and rats that rapamycin preserves muscle function and mass with aging and prevents sarcopenia. I’m not aware of any human data yet.

M. Kaeberlein: In mice, yes. Metformin appears to have little to no effect on lifespan in mice in longer-lived strain backgrounds, although it does improve some measures of metabolic health during aging. In humans, we don’t know yet, but the metformin data is fairly compelling and more extensive than rapamycin, simply because more people have been taking metformin for many years.

M. Kaeberlein: We get our rapamycin from LC Labs for our yeast, worm, and mouse work: https://lclabs.com/products/r-5000-rapamycin. For human or dog studies, we use the generic Rapamune or sirolimus available from any pharmacy.

M. Kaeberlein: This hasn’t been studied in people as far as I know. In mice and rats, rapamycin preserves muscle function and mass during aging.

M. Kaeberlein: All dogs are eligible and you can participate by going to www.dogagingproject.org and clicking the ‘nominate my dog’ button. The only restriction is that, for now, we can only accept one dog per household.

M. Kaeberlein: This is still a bit of a controversial question in the veterinary literature but I’d say the best evidence suggests a small increase in lifespan is associated with sterilization. What seems clear is that sterilization changes the disease risk in both directions – some diseases become more prevalent and some less prevalent. There is, as you might suspect, also a sex-dependent effect. The largest study addressing this question is here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629191/. I think our Longitudinal Study of Aging will be able to help resolve some of the remaining questions in field around this topic in a few years.

M. Kaeberlein: It depends on whether you are talking about mice or humans. In humans, we don’t know much about efficacy of rapamycin for aging. Exercise clearly “works” in the sense that people who exercise tend to live longer and be healthier. Fasting gets a lot of attention, but it’s still unclear how effective that is in people. In mice, caloric restriction and rapamycin are comparable in magnitude and breadth of effects across many organs and tissues. Severe CR (50%) appears to be slightly better than rapamycin at increasing lifespan. Exercise has minimal effects on lifespan in mice but does improve health. Most fasting experiments in mice are not isocaloric, so they are really CR. It’s unclear whether isocaloric fasting, intermittent fasting, or time-restricted feeding really have any significant benefits in terms of aging in mice. My guess is they probably are modest at best (again I’m talking about isocaloric nutritional interventions).

M. Kaeberlein: The simple answer is that global protein synthesis goes down and autophagy goes up. It’s obviously more complicated than that, and it’s unclear whether therapeutic doses – even at the higher organ transplant levels – have this effect generally across many tissues in mammals. One model that is gaining popularity is that the cyclical dosing of rapamycin (once per week for example) is actually better at maintaining productive autophagy than daily dosing, because you need cycles of protein synthesis (high mTOR) to rebuild the autophagic machinery periodically.

M. Kaeberlein: This seems unlikely, as the doses being used probably don’t significantly impair protein synthesis and seem to preserve muscle mass and function during aging in mice and rats.

M. Kaeberlein: There is not any good data on this yet in dogs, although people have very strong opinions. We expect that the data from our longitudinal study of aging will help provide some answers that can better guide recommendations to pet owners and also provide insights into interactions between nutrition and aging in the ‘real world’.

M. Kaeberlein: The short answer is that we evaluated what was known about dosing for efficacy and side effects in mice, dogs, and humans and came up with a dose that we were confident would be safe in companion dogs and hopefully provide efficacy for the aging endpoints we are studying. We have performed two short randomized, clinical trials testing three different doses. We have also been guided by the Canine Oncology Trials Consortium studying rapamycin in dogs with cancer as to dosing. The once weekly schedule is based largely on data from humans that once weekly dosing seems to reduce side effects while maintaining efficacy, at least for restoration of age-related immune decline.

M. Kaeberlein: Yes, several studies have shown that rapamycin can increase lifespan and improve health during aging in both male and female mice, although rapamycin seems to be metabolized differently in male and female mice such that the effective dose – and response – is higher in females compared to males provided with the same dose. I’m not aware of any data that something similar happens in dogs or people, with respect to sex. Several genetic models of mTORC1 depletion have been developed and found to delay aging. Veronica Galvan’s lab has done some elegant work with depletion of mTORC1 in the brain showing protective effects for normative cognitive aging and in Alzheimer’s disease models.

M. Kaeberlein: There are several downstream mechanisms that likely contribute. In mammals, I think the anti-inflammatory effects are probably underappreciated. Exactly how this works is still being uncovered, but it’s clear that rapamycin can potently suppress the so-called ‘senescence associated secretory phenotype’ which includes many inflammatory cytokines. Increases in autophagy, improved mitochondrial function, and changes in translation and transcription have been shown to be important in invertebrate models and also likely play a role in effects of rapamycin on mammalian aging.

M. Kaeberlein: I suppose, but it’s not clear to me what those problems would be. I think you could make an argument that what we’ve done during the 19th and 20th century – increasing life expectancy without slowing aging – has done this. We have a lot more people with Alzheimer’s disease today than we did a century ago, for precisely this reason.

M. Kaeberlein: We’re just at the idea stage, but yes, it is my hope and expectation that we will be able to test other interventions in companion dogs in the future.