Could Metformin be Used as Anti-Aging Therapy?
What is Metformin Used for?
Metformin is the most widely-prescribed oral hypoglycemic medication for type 2 diabetes worldwide.
In 1922, synthesis of metformin and related biguanide compounds phenformin and buformin was achieved by Werner and Bell, paving the way for metformin to attain widespread use in humans as first-line therapy for type 2 diabetes (T2D) worldwide. Metformin also has proven roles in prevention of diabetes, in treatment of the polycystic ovary syndrome (PCOS), and in helping individuals with diabetes prevent weight gain or even lose weight.
Does it have Anti-Aging Properties?
Emerging evidence indicates that metformin has favorable effects on health beyond those associated with improvement in glycemia. Observational studies suggest that diabetic individuals treated with metformin manifest a survival benefit even when compared to non-diabetic controls.
Metformin not only reduces cardiovascular disease incidence in patients with type 2 diabetes, it similarly reduces atherosclerotic burden in non-diabetic individuals at risk for the disease. Observational data in humans further support a role for metformin in prevention of aging related decline and cancer, an area of immense clinical interest.
Is Aging a Disease?
Aging is often referred to as a risk factor for age-related diseases and is sometimes described as the “sum of age-related diseases.” The WHO now formally recognizes aging as a disease in the latest version of the International Classification of Diseases (ICD-11).
The formal recognition of aging as a disease is meaningful for the development of future therapeutic interventions or strategies targeting aging and aging-related diseases.
Metformin has been explored as an anti-aging agent in model organisms and humans, given its excellent safety record for over six decades in the clinic, well-documented beneficial properties in cardioprotection and potential value in cancer prevention and treatment.
How Does it Works?
Even though the drug has been used for more than 60 years, its antihyperglycemic mode of action remains incompletely characterized. Recent advances have revealed multiple cellular effects of metformin that may be relevant for its effects both on metabolism and aging.
It is widely accepted that the mitochondrion is a primary target of metformin responsible for its anti-glycemic effect. In line with early studies indicating a primary effect of metformin on complex I of the mitochondrial electron transport chain, recent work also provides strong genetic evidence that metformin inhibits cancer cell growth through its actions on complex I. By targeting complex I, metformin lowers the relative energy charge of the cell, raising adenosine monophosphate (AMP) levels relative to adenosine triphosphate (ATP).
One of the effects of improving insulin sensitivity is that metformin also lowers oxidative stress and, as we just mentioned, inflammation. These are two of the key factors in the aging process. Oxidative stress happens when there’s damage to the cells by free radicals, which are unstable molecules, and is a normal part of aging. Oxidative stress is a cause of inflammation, which is involved in age-related disease and death.
Metformin lowers oxidative stress and inflammation through its effects on activating the enzyme called AMPK (adenosine monophosphate-activated protein kinase or AMP-activated protein kinase). By lowering oxidative stress and inflammation, metformin may fight some of the aging effects that happen with those two factors.
Anti-cancer effects of Metformin
Recently, it was widely proposed that metformin could be protective against neoplastic diseases. The anti-cancer activities of metformin are associated with both indirect and direct effects of this drug. The indirect mechanisms result from general modifications of blood glucose and insulin levels, which could influence the survival of cancer cells.
It is reported that insulin and insulin-like growth factor 1 (IGF-1) can promote tumorigenesis by stimulating the proliferation of epithelial cells. Decreasing the insulin level as a result may prevent such neoplastic activity.
Metformin can also affect the inflammatory processes that are reported to play a significant role in tumor progression. Blocking of transcription factor nuclear factor-κ B (NF-κ B) activity mediated by metformin results in reduced secretion of pro-inflammatory cytokines. Additionally, metformin has been reported to activate the immune response to cancer cells.
Metformin and the Microbiome
The microbiota has been reported to have strong associations with many age-related disorders, such as T2D, obesity, and cancer. In certain organisms, metformin may impede aging and age-related disorders by modulating the microbiome.
Studies in rodents have focused on whether metformin modulation of the microbiota affects metabolism rather than aging per se.
Studies in humans have yielded important findings on metformin’s microbiota effects:
- Metformin increases the population of bacteria good at producing short-chain fatty acids that contribute to weight loss and inflammation suppression in T2D individuals.
- Microbial shifts following metformin use may account for the antiglycemic effect of metformin and its accompanied side effects in people with T2D.
Extension of Human Longevity
In addition to the lifespan-promoting activity of metformin in various model organisms, metformin has the capability to reduce the mortality rate of diabetic patients from all causes independent of its effect on diabetes control.
While it is likely based upon data in diabetics that the drug is safe and generally well tolerated, it is unclear whether healthy individuals will manifest a net benefit on aging in the same way that diabetic subjects do.
Metformin is approved for treatment of T2D, but its therapeutic potential in the treatment of other conditions has been recently reported, in particular its anti-aging and anti-cancer effects seem to be promising. Further studies are required to know if it can be widely used in other individuals, including those who don’t have diabetes.
Soukas AA, Hao H, Wu L. Metformin as Anti-Aging Therapy: Is It for Everyone?. Trends Endocrinol Metab. 2019;30(10):745-755. doi:10.1016/j.tem.2019.07.015
Podhorecka M, Ibanez B, Dmoszyńska A. Metformin – its potential anti-cancer and anti-aging effects. Postepy Hig Med Dosw (Online). 2017 Mar 2;71(0):170-175. doi: 10.5604/01.3001.0010.3801. PMID: 28258677.
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