In a recent study conducted by researchers at the Novartis Institutes for Biomedical Research in Massachusetts, inhibition of mTOR complex 1 boosts the immune system of aged people, decreasing their yearly rate of infections as well as increasing their response to an influenza vaccine [1].

Study summary Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.

The problems of an aging immune system

The immune system is only one of the many things that go downhill as we age, yet it is vitally important and not simply because it keeps us free from infections. Immune surveillance is also responsible for the clearance of senescent cells, which are associated with a large array of aging-related pathologies, and of cancer cells as well. The decline of the immune system, also known as immunosenescence, is one of the reasons why cancer rates, as well as the rates of innumerable other ailments, skyrocket with age. Unfortunately, immune decline starts in our infancy and gets worse and worse with the passing of time.

mTOR and the new study

Researchers at the Novartis Institutes for Biomedical Research investigated the possibility of boosting the aged immune system through the suppression of complex 1 of the mTOR pathway.







mTOR, the mammalian Target of Rapamycin, also known as the mechanistic Target of Rapamycin, is the core component of two protein complexes, namely mTOR complex 1 (TORC1) and mTOR complex 2 (TORC2). It is involved in cell growth and proliferation, cell motility, protein synthesis, autophagy, transcription, and the activation of insulin receptors and IGF-1 receptors. While experiments on mice have revealed that TORC2 inhibition leads to adverse effects, such as hypercholesterolemia and hyperglycemia, TORC1 inhibition has been associated with healthspan and longevity benefits in different model organisms, including mice. There are many hypotheses as to why this is the case, one of which relies on antagonistic pleiotropy; higher TORC1 activity may be beneficial early in life but deleterious in old age, when it may contribute to the onset of several pathologies, such as cancer, Alzheimer’s, and Parkinson’s.

Researchers in general are becoming increasingly convinced that, in order to eradicate the diseases of aging, the only way is to attack the processes of aging itself, which are what drives aging-related diseases in the first place. Thus, the best way to prevent immunosenescence and decrease an ever-growing share of the global population’s vulnerability to both communicable and noncommunicable diseases may be to rejuvenate the immune system. This is what Novartis researchers attempted to do in their study’s human clinical trial.

Elderly volunteers aged 65 and over were orally administered either one of two TORC1-inhibiting drugs, a combination of both, or a placebo over the course of six weeks. Participants were then monitored for a year to assess the effects of the drugs.

While participants did report side effects, these were often minor and limited to a small percentage of subjects. Patients receiving either or both drugs had a reduced rate of infections compared to the controls, with drops of up to 40% in the case of patients receiving both inhibitors. Additionally, subjects who received the drugs appeared to have an enhanced immune response to a vaccine for common influenza strains (H1N1, H3N2, and B). Again, the effect was more pronounced when both drugs were administered; recipients had up to a 20% higher antibody concentration compared to controls.

It is also worth noting that patients were administered low doses of the drugs, but higher doses might not be indicated; as the researchers pointed out in the study, excessive amounts lead to the opposite effect, suppressing immune cell proliferation and thereby increasing the risk of infections.







Considering that respiratory tract infections are among the leading causes of death among the elderly and that their weakened immunity makes them vectors for spreading infections, having a safe, easy-to-take drug that enhances immune activity may be a big deal for people who are at least middle-aged.

One limitation of this study is that the assessment of infections was self-reported by the subjects, which might raise questions about reliability. However, the researchers note that the increased immune response to a vaccine backs up the self-reported assessment and that previous research suggests that elderly subjects are able to accurately self-report infections.

Conclusion

This study certainly represents good news, but further research will be needed to confirm the usefulness of TORC1-inhibition to restore immune function and to assess how these drugs work in even older people and people with pre-existing conditions.

Literature







[1] Klickstein, L. B., Glass, D. J., Quinn, D., Zhou, W., Shavlakadze, T., Watkins, M., Kulmatycki, K., Beibel, M., Roma, G., Hockey, H. P., Morris, M., & Mannick, J. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. Science Translational Medicine, 10(449).