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.