Abstract
The growing epidemic of many age-related chronic diseases, such as cardiovascular diseases, diabetes, cancer, and neurodegenerative diseases, especially Parkinson’s and Alzheimer’s disease, places an increasing burden on the healthcare systems worldwide. In recent years, efforts to manipulate the consequences of aging have yielded some success, and naturally, identifying effective ways to slow down or even reverse aging has become increasingly popular. Importantly, existing drugs can be repurposed for anti-aging effects. Studies from model organisms and early stage human clinical trials have found that metformin and rapamycin, which respectively are an effective anti-diabetic medication and an immunosuppressant, have promising results in slowing aging and treating age-related diseases. These findings point to the possibility that these two anti-aging drug candidates, and especially their derivatives which may reduce side effects, are likely to become the first genuine rejuvenation medications to achieve healthy aging. Here, we present knowledge on the mechanisms that are involved in the anti-aging effect of the two molecules, followed by an outline of a host of potential aging-related clinical applications. We finally provide insights on the considerations and further directions for the development of anti-aging drugs.
Introduction
Advances in nutrition, sanitation and, hygiene, together with the use of antibiotics and vaccines, have resulted in a dramatic increase in life expectancy for people across the globe. Over the last two centuries, the global life expectancy has nearly doubled, increasing from around 30 years in 1800 to around 70 in 2015 1, 2. By 2030, the life expectancy in many countries is projected to exceed 85 years—e.g. women in South Korea will likely break the 90-year barrier3. Globally, one quarter of the population is expected to be in their sixties or older in 2050 4.
Nonetheless, the unprecedented longer life expectancy and the expanding aging population have led to an epidemic of chronic age-related diseases such as cancer, cardiovascular diseases, Type 2 diabetes, and dementia, including Alzheimer’s disease (AD) and Parkinson’s disease (PD)5. These diseases are all known to impair the quality of life for individuals. Additionally, the staggering number of people who live with these aging-associated diseases place a considerable burden on the social, economic, and healthcare systems worldwide. Therefore, from both an individual and a societal standpoint, there is pressing need to combat the challenges posed by age-related diseases and increase the health span of humans 6, 7.
In the last few decades, intensive efforts have been made to improve the clinical outcomes of age-related diseases, such as diabetes and many types of cancer, but not AD. However, those efforts have been largely unsuccessful in preventing the fast-growing prevalence of multiple co-existing conditions, defined as more than two co-existing chronic conditions in one individual. The majority of the elderly population (individuals aged 65 and above) now are affected by chronic multi-morbidities, whereas the current delivery of health services and the research interests have continued to focus on combating the chronic diseases individually 8. Clearly, this insular approach is inefficient for preventing the development of age-related diseases more broadly 9, 10.
In contrast, aging mechanisms that account for the phenotypic characteristic of old age, such as sarcopenia, frailty, impaired metabolic profiles, and neurodegeneration, have been shown to be the underlying determinants of many different chronic diseases11. Therefore, modifying the mechanisms of aging directly seems to be a more productive approach to fundamentally curb the escalating epidemic of chronic diseases.
Although aging has historically been considered an irreversible process; this perception has already started to change. Encouragingly, emerging clinical trials of anti-aging drugs have shown promising results in various animal models 12. Early human trials have begun, with hundreds of anti-aging drug candidates already registered for clinical trials 13. It is important to clarify that the focus of these studies is not to eliminate aging and pursue immortality, but instead to extend healthspan, the length of time during which people are living disease-free and in vitality. The current body of promising animal studies, and commercial interests, have resulted in swift growth of biotech companies that focus on developing anti-aging therapeutics commercially 14. The anti-aging approaches piloted by these start-ups range from modern artificial intelligence-driven methods to life-extension drugs15.
Among all the anti-aging strategies, calorie restriction (CR) without malnutrition is one of the most reliable approaches in expanding both lifespan and health-span in various vertebrate and non-vertebrate species. While the exact molecular mechanisms associated with CR’s health benefits remains not fully understood so far, emerging evidence suggests that CR’s beneficial effects in slowing down the aging process can be attributed to the nutrient-sensing pathways (NSP), including the mTOR, AMPK, and IIS pathways. Under CR, the NSPs trigger an array of processes to promote autophagy, a potent cellular mechanism that degrades and recycles dysfunctional components and thus maintain the cellular nutrient and energy balance. However, CR is difficult to sustain and implement since individuals must remain in a state of hunger and endure feelings of starvation, fatigue, and irritations. Besides, the individuals who practiced CR have been reported to be more susceptible to viral infections 16 and resistant to wound-healing 17, both of which impede its widespread use.
To circumvent its impracticality, calorie-restriction mimetics (CRM), drugs that up-regulate autophagy by triggering the NSPs without actually restricting calorie intake, are considered worthy of investigation. Typical pharmaceutical CRMs include resveratrol, aspirin spermidine, metformin, and rapamycin 18. Among them, both rapamycin and metformin have been used extensively in clinical settings and have well-documented side effects. While they have distinct prescribed use in clinical setting, they have been investigated for many off-label uses for their pleotropic effects against aging, cancer, and cardiovascular diseases.
In this review, we first present a brief overview of the mechanisms of nutrient sensing pathways. We then review the pre-clinical and clinical studies on the effects of metformin and rapamycin in anti-aging, and its association with nutrient-sensing pathway. Finally, considerations and insights for the future directions of anti-aging drug development are offered to guide the next wave of research in the anti-aging field.