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During this episode of Longevity by Design, Dr. Joan Mannick explains how mTOR influences the aging process. She explains that this evolutionarily conserved protein is involved in several cellular functions in the body and acts on longevity-promoting pathways like autophagy. Dr. Mannick also discusses the connection between mTOR and the immune system, sharing her research on how low-dose mTOR inhibitors can upregulate antiviral immunity, creating an opportunity for more targeted vaccines for older adults. After extensive research on mTOR across many species, Dr. Mannick shares impressive insight into how mTOR inhibitors like rapamycin can promote longevity. Tune in to learn more about the latest research in the field.
Dr. Joan Mannick is a medical doctor, researcher, and expert in aging. She has served as faculty member at Harvard Medical School and University of Massachusetts Medical School. She received her MD from Harvard Medical School. and completed her residency at Brigham and Women's Hospital. She is currently CEO at Tornado Therapeutics where they develop safer, more effective mTOR inhibitors to extend human healthspan.
Mammalian target of rapamycin (mTOR) is a protein involved with several cellular functions, including regulating cell proliferation, autophagy, and apoptosis. [1] mTOR is an evolutionarily conserved protein across eukaryotes—it is present in yeast, flies, worms, mice, and humans. Further, mTOR regulates how our bodies respond to nutrients; mTOR turns on when we eat and turns off during fasting.
Not only is mTOR present in all eukaryotic organisms, it also regulates their longevity. Dr. Mannick notes the extensive body of literature on this protein that confirms mTOR as a validated mechanism of lifespan regulation. “Whether you inhibit this single protein genetically or with a drug called rapamycin, lifespan is extended. This holds true for yeast, worms, flies, and mice,” she says. And because mTOR inhibition extends these species' lifespan, it may also be advantageous in humans, as noted by Dr. Mannick.
Rapamycin is a natural product found in soil, initially developed as an antifungal medication. Scientists found that in addition to inhibiting fungal growth, rapamycin also inhibits the replication of other cell types, including T cells and cancer cells. Now, derivatives of rapamycin are approved for cancer treatment.
mTOR is used by the body to produce proteins and lipids. This protein is activated after consuming food and produces macronutrient building blocks so T-cells, cancer cells, and fungi can proliferate. Rapamycin inhibits mTOR activity by binding to it and destabilizing it. Therefore, rapamycin can inhibit proliferation across many cell types since mTOR activity is needed in order for them to grow and divide.
Fasting inhibits mTOR activity. The inhibition of mTOR signals protective pathways to be up regulated—one example being autophagy. This connection between mTOR and autophagy suggests that some of the health benefits associated with intermittent fasting may be attributed to mTOR inhibition.
mTOR activity is dysregulated with age; it becomes hyperactive and doesn't respond to fasting. Dr. Mannick explains that when older mice fast, they don't turn down mTOR anymore, and protective pathways aren't up regulated. Therefore, administering an mTOR inhibitor like rapamycin to an older population may be beneficial to turn the hyperactive mTOR down, mimicking a younger level.
To date, Dr. Mannick’s team’s work examines the effect of mTOR on improving the aging immune system’s function. She explains that although this seems counterintuitive since mTOR is approved to suppress immune function, her trials have shown that the use of very low doses or intermittent doses of mTOR inhibitors actually enhances immune function.
Individuals aged 75 may benefit the most from mTOR inhibitors. “We started with individuals aged 65, but where we really start seeing benefits is in those 75 and above. That’s when the immune system shifts to an older age. Around age 75, there seem to be immune function deficits, and we observe better efficacy of mTOR inhibitors,” says Dr. Mannick.
Dr. Mannick notes that whether an individual will have immune dysfunction between the ages of 65 and 75 varies. After 75, there is a more uniform decline in immune function. “If you look at the all-cause mortality in individuals aged 65 to 75, they seem to experience the same rate of death throughout each year. Those 75-85 or 85+ show peaks of death during the winter due to cold and flu season, which typically isn’t observed in the younger end of the cohort. Essentially, by 75, everybody has a decline in immune function,” she says.
Dr. Mannick’s research investigated the impact of a flu vaccination manipulated by mTOR in older adults. In this trial, her team administered an mTOR inhibitor to older adults at unusual doses that they suspected would not suppress the immune system. They analyzed the participants' response to the flu vaccination and found that those receiving the mTOR inhibitors had fewer reported respiratory tract infections than the placebo group.
This study was novel in that it targeted aging biology in a human and showed functional improvements in an aging organ system.
Following the success of this trial, Dr. Mannick and her team postulated that if this method enhances the response to a flu antigen, it may enhance the response to additional antigens. Her team found that those receiving flu vaccinations containing mTOR inhibitors had fewer all-cause infections than a placebo group.
Dr. Mannick’s team has repeatedly shown that treating older patients with low-dose mTOR inhibitors upregulates antiviral immunity. Because antiviral immunity declines naturally as we age, Dr. Mannick sees this as an opportunity to create more targeted vaccines for older adults. In fact, her team ran an mTOR trial aimed to prevent severe COVID-19 in nursing-home residents.
While the data surrounding rapamycin and other mTOR inhibitors look promising, Dr. Mannick cautions that there is still a lot we don't know about mTOR inhibitors yet. "I don't want people to think we have fully cracked this nut. We're working through it, and we're getting closer to understanding how to use these drugs to have clinical benefit, but there is still work to do," she explains.
Dr. Mannick reiterates her data-driven approach to therapeutic interventions targeting aging, noting that there's yet to be a solid solution. In the meantime, she notes that the best course of action to target aging is to exercise, sleep, and eat a healthy balanced diet.
Dr. Mannick notes an interesting phenomenon she has experienced in her anti-aging trials—the placebo effect. "Individuals in an anti-aging trial who are receiving the placebo will report feeling like they are less old—they have more energy, they'll say their vision hasn't been this good in 20 years, and they are suddenly hearing; meanwhile they are on placebo. It is hugely important in these studies to make sure there is a placebo group because, without a placebo, you can not say for certain if your intervention is doing anything significant," she cautions.
Dr. Mannick’s top tip for healthspan is to do all things in moderation and enjoy life. She concludes that she eats a balanced diet, gets adequate sleep, and exercises to promote overall health.
References:
[1] Zou, Z., Tao, T., Li, H. et al. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci 10, 31 (2020). https://doi.org/10.1186/s13578-020-00396-1