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The Anti-aging Drugs that Are Undergoing Clinical Trials

Two anti-aging drugs that are under development and some commonly used drugs can act as geroprotectors in animal models. The Intervention Testing Program (ITP), supported by the National Institute of Ageing, has identified five drugs that reproducibly increase the lifespan of genetically heterogeneous mice, including rapamycin, acarbose, nordihydroguaiaretic acid, 17-α-estradiol and aspirin. Some of these drugs also improve healthy longevity indicators in certain tissues of animal models. Other drugs found to extend the lifespan of rodents include metformin, drugs targeting angiotensin-converting enzymes and aldosterone receptors, and sirtuin activator SRT2104 and SRT1720. Further research is needed to verify whether these drugs can act as real anti-aging agents in model organisms.


It still remains a problem as to how to test these interventions and ultimately use them in the human body. Geriatric science predicts that anti-aging therapies will simultaneously improve or prevent multiple age-related diseases and conditions. Therefore, clinical trials that test this hypothesis should use clinical outcomes that essentially depend on multiple age-related diseases or symptoms. Such examples include multiple disorders, a combination of several age-related chronic diseases; multifactorial age syndromes such as debilitation or spasms; resilience to healthy stress factors such as surgery or infection. Multiple disorders and weakness are also widely included in age-related risk measurements to provide a basis for clinical decision making. Other clinical trial measurements that may be useful include grip strength, gait speed, timed standing-walking, and activities of daily living.


These clinical measures of aging may help to select patients with higher age-related risks to receive intervention. For example, as age increases, the risk of multiple illnesses increases dramatically. However, suffering from a chronic disease can increase the risk of developing another chronic disease by several times. The potential anti-aging effects of at least five major types of drugs are currently being tested in humans.


(1) Metformin


Metformin is a widely used anti-diabetic drug that has been found to target a variety of aging molecular mechanisms. A retrospective analysis of diabetic patients receiving metformin showed that metformin prolonged the lifespan of diabetic patients compared with patients without diabetes. In randomized clinical trials, metformin prevented diabetes, improved cardiovascular risk factors, and reduced mortality. Epidemiological studies have shown that the use of metformin may also reduce the incidence of cancer and neurodegenerative diseases.


(2) Rapamycin analogue


The compound identified by ITP that may have the greatest impact on life is rapamycin. Rapamycin inhibits the TOR pathway, prolongs the lifespan of yeast and Drosophila, and increases the average lifespan of mice with multiple genetic backgrounds. Rapamycin, also known as sirolimus, and its analog, everolimus, have been approved clinically as immunosuppressive agents for solid organ transplantation. Healthy elderly people have improved their immune response to influenza vaccine after six weeks of non-immunosuppressive dose of everolimus. A subsequent clinical trial found that a six-week low-dose of everolimus plus a second TOR inhibitor improved the vaccine response and reduced the infection rate by more than a third in the following nine months.


(3) Senolytics


Drugs that selectively eliminate senescent cells have enormous anti-aging potential in animal models. Some of these drugs are natural products, while others are synthetic small molecules. More and more biotech companies and research laboratories are developing new or modified senolytics, which are just beginning to be tested for safety in humans. So far, there have been no results on efficacy.


(4) Sirtuin activator


The sirtuin-activating compound (STAC, also known as sirtuin activator) enhances sirtuin activity and increases the healthy lifespan of mice and non-human primates. However, confusion has been observed in clinical trials. Resveratrol (a natural STAC) and SRT1720 (an early synthetic STAC) showed encouraging results in preclinical trials, but failed in clinical trials due to lower bioavailability and potency and limited target specificity. To date, the most promising synthetic STAC is SRT2104, a highly specific SIRT1 activator. This compound has completed several small clinical studies on the effects of cardiovascular and metabolic markers and is undergoing larger clinical trials.


(5) NAD+ precursor


NAD+ precursors such as nicotinamide ribose and nicotinamide mononucleotides are intended to complement the age-related decrease in cellular NAD levels. In animal models, both precursors exhibit activity against a variety of aging-related diseases. Several companies currently sell nicotinamide ribose and nicotinamide mononucleotides online. Although these supplements increase the level of NAD in the human body, they have not been proven to be effective or anti-aging to humans.


We are now entering an exciting age of aging research. This era offers unprecedented hope for an increase in human health and longevity: according to new scientific findings, it is possible to prevent, delay or, in some cases, reverse many aging lesions. Whether this era is expected to increase the maximum life expectancy of mankind remains an open question.

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