In the quest for an anti-ageing drug

As life expectancy rises, ageing is becoming a major health challenge, often linked to chronic diseases like heart ailments, cancer, and dementia. Even as research around drugs like Metformin and Rapamycin offers hope for extending healthspan, their broader use as anti-ageing treatments requires further investigation, writes Dr Praveen Kumar Kaudlay

The global average lifespan is steadily increasing, with most people today expected to live well into their sixties and beyond. By 2030, it is projected that one in six people worldwide will be aged sixty or older.

Understanding ageing

Ageing is characterised by a progressive decline in physiological function. Biologically, it results from accumulated molecular and cellular damage over time, leading to a gradual reduction in both physical and mental capacities, an increased risk of disease, and ultimately, death. However, these changes do not occur in a strictly linear fashion. Research suggests that the proportion of life spent in good health has remained relatively constant, implying that longer lifespans may often be associated with additional years of poor health.

In 1980, Dr James F Fries, a physician at Stanford University specialising in chronic disease and ageing, proposed the concept of a “compression of morbidity”. According to this theory, advances in health could enable most people to remain healthy until a certain age — possibly around 85 — after which they would experience a brief period of illness before passing away.

The consequences of ageing

Ageing is closely linked to chronic diseases, many of which can be severely debilitating. It is the most reliable predictor of chronic conditions such as atherosclerotic heart disease, stroke, cancer, dementia, and osteoarthritis. If one or more drugs could theoretically slow the biological process of ageing, they could also reduce the risk or severity of these associated chronic illnesses, fundamentally altering how we manage health in later life.

Targetting healthspan

Dr Brian Kennedy, a distinguished professor of physiology and biochemistry at the Yong Loo Lin School of Medicine, National University of Singapore (NUS), has focused much of his research on understanding the biology of ageing and translating these discoveries into methods for delaying, detecting, preventing, and treating ageing and related diseases. He explains that there is overwhelming evidence that life can be extended by targetting nutrient-sensing pathways, such as the insulin/insulin-like growth factor (IGF) pathway and the mechanistic target of rapamycin (mTOR) signalling pathway. These pathways have been studied in animal models where lifespan has been extended through genetic modifications or drugs. Rapamycin, an mTOR inhibitor, was originally used as an immune suppressant for kidney transplant patients and has now emerged as one of the most compelling pieces of evidence supporting the targetting of ageing.

Metformin: Beyond Type 2 Diabetes

Metformin, the most widely used anti-diabetic drug, has roots dating back to the 17th century. The extracts of French Lilac (Galega officinalis), which contain compounds similar to Metformin, were used to treat ailments such as plague, fever, and snakebites, although these compounds were too toxic for human use. In 1957, French physician Jean Sterne achieved a major milestone by obtaining approval for Metformin as an anti-diabetic drug under the brand name Glucophage. Since then, Metformin has become a first-line treatment for type 2 diabetes (T2D) and has been proven to help prevent diabetes, treat polycystic ovary syndrome (PCOS), and even assist diabetic patients in maintaining or losing weight.

Observational studies suggest that Metformin offers a survival benefit for diabetics, and it has been shown to reduce atherosclerosis (the narrowing of blood vessels) in non-diabetic individuals at risk for the condition. The UK Prospective Diabetes Study (UKPDS) supports Metformin’s role in effectively managing diabetes and reducing cardiovascular risk. Clinical studies also indicate that Metformin may reduce cognitive decline and mortality in diabetics compared to non-diabetics.

Ageing as a disease

The World Health Organisation (WHO) has formally recognised ageing as a disease in the latest International Classification of Diseases (ICD-11). This recognition could pave the way for meaningful interventions targetting ageing and age-related diseases. It opens the possibility of using drugs already licensed for other conditions to improve the healthspan of healthy individuals. The TAME trial (Targeting Ageing with Metformin) is investigating whether Metformin — already proven to be safe and licensed for use in diabetes — can affect age-related diseases. However, the specific dosage of Metformin needed to achieve this goal has not yet been established.

It is unclear exactly how Metformin influences ageing, but researchers believe it targets several hallmark processes of ageing that occur at the cellular, chromosomal, and molecular levels. These processes contribute to heart disease, diabetes, cancer, and dementia. Metformin also has anti-inflammatory effects, which may play a role in its potential anti-ageing benefits.

Dr Kennedy cautions that the benefits observed in diabetics with high blood sugar and obesity may not necessarily apply to individuals with normal blood glucose levels. Ageing is a heterogeneous phenomenon, and people within the same population may react to Metformin differently.

The uncertainty of widespread use

Long-term use of Metformin in type 2 diabetes patients is known to cause vitamin B12 deficiency, although it is less likely to result in anaemia or nerve damage, which are common outcomes of B12 deficiency. Metformin also increases lactate levels, leading to a rare but serious condition known as lactic acidosis, which can be fatal if it becomes severe. Other common side effects include diarrhoea, nausea, flatulence, indigestion, and abdominal discomfort.

A major concern with widespread Metformin use for anti-ageing purposes is whether it will have the same efficacy for everyone. Not all diabetic patients respond equally well to the drug, and it is possible that individuals with normal blood glucose levels may not experience the same benefits. Additionally, there are environmental concerns about the potential impact if millions of people take Metformin and excrete the unchanged drug into the ecosystem.

For now, experts like Dr Kennedy do not recommend using either Rapamycin or Metformin as anti-ageing drugs until clinical trials confirm their benefits.

(The author is a consultant haemato-oncologist with a special interest in stem cell transplantation at Royal Wolverhampton NHS Trust, UK. He can be reached at [e-mail].)