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EXPLORING THE ANTI-AGEING POTENTIAL OF GLP-1 ANALOGUES
EXPLORING THE ANTI-AGEING POTENTIAL OF GLP-1 ANALOGUES
Dr Anish Kotecha and Professor Steve J. Davies explore a promising avenue in longevity research
GLUCAGON-LIKE PEPTIDE-1 (GLP-1) analogues have garnered significant attention for their therapeutic benefits in managing type 2 diabetes mellitus and obesity1. However, emerging research suggests that these molecules may hold promise beyond their primary indications, offering exciting potential in the realm of anti-ageing and longevity. As humans continue to make advances in science and medicine, lifespan expectancy continues to rise. However, increased longevity does not necessarily equate to increased health span — the number of years spent in good health. Research now suggests that along with extending our life expectancy, targeted interventions may help compress morbidity, delaying the onset of age-related diseases and disorders, allowing us to not just live longer but also healthily2. One key intervention supported by mounting evidence is intentional weight loss, particularly in those carrying excess adiposity.
GLP-1 analogues, weight loss and anti-ageing
Obesity is considered a state of chronic, low-grade systemic inflammation3. This inflammation is implicated in cellular ageing via increased oxidative stress and telomere attrition4. Consequently, excess adiposity significantly increases the risk of developing numerous chronic diseases that predominantly afflict older populations.
With respect to interventions, animal studies reveal that calorie restriction is one of the few interventions associated with reduced mortality and longevity5. Whilst these studies are not entirely translatable to humans, epidemiological data reveal healthy longevity in communities where calorie restriction is common practice6. More recently, however, the emergence of GLP-1 analogues has heralded a new paradigm in not just glycaemic control but also weight loss and mortality7 Glucagon-like peptide-1 (GLP-1) is a hormone released by the small intestine and, as well as regulating insulin secretion, GLP-1 also acts centrally in appetite regulation. However, physiological GLP-1 is short-acting, yet GLP-1 analogues such as liraglutide, semaglutide and tirzepatide have a much longer duration of action. They are associated with improved glycaemic control and weight loss8. Whilst studies reveal that GLP-1 analogues are associated with improved glycaemic control and weight loss in subjects with type 2 diabetes, treatment is also associated with reduced cardiovascular risk9. Beyond diabetes, the 10-20% weight loss seen with GLP-1 analogues is also associated with reduced cardiovascular risk in non-diabetic, obese and overweight subjects10. Side effects are predominantly gastrointestinal but usually in the initiation or dose escalation phase. They are transient and usually tolerable11. The latter observation is remarkable in obesity and so offers the intriguing potential of longevity in association with GLP-1 analogue therapy through modulation of several age and obesity related mechanisms.
Studies reveal that GLP-1 analogues can improve mitochondrial biogenesis, reduce reactive oxygen species production, and upregulate antioxidant defence. These actions may contribute to the preservation of cellular integrity and functionality, potentially counteracting age-related deterioration.
Mitigating age-related inflammation with GLP-1 analogues
GLP-1 analogues exhibit anti-inflammatory properties, which could mitigate age-related inflammatory processes implicated in chronic diseases12. Chronic low-grade inflammation is a hallmark of ageing and is associated with an increased risk of age-related diseases, such as cardiovascular disorders, neurodegenerative diseases, and certain cancers13. By modulating inflammatory signalling pathways and regulating immune cell function, GLP-1 analogues may play a role in reducing the detrimental effects of inflammation on ageing14. Similarly, a progressive decline in mitochondrial function, leading to increased oxidative stress, inflammation and cellular damage, is associated with accelerated ageing15. Studies reveal that GLP-1 analogues can improve mitochondrial biogenesis, reduce reactive oxygen species production, and upregulate antioxidant defence16. These actions may contribute to the preservation of cellular integrity and functionality, potentially counteracting age-related deterioration.
Neuroprotection and cognitive health
In consequence, GLP-1 analogue therapy appears to have roles beyond weight loss and diabetes. Studies reveal potential for neuroprotection, with preclinical studies showing enhanced neuronal survival, synaptic plasticity and reduced neuroinflammation17. Liraglutide improved cognitive function and reduced neuroinflammation in a mouse model of Alzheimer’s disease, potentially by modulating histone acetylation and deacetylase expression18 and has been shown to improve non-motor symptoms, mobility, and quality of life in Parkinson’s disease patients19. With respect to the latter, treatment with the GLP-1 analogue, lixisenatide, has been shown to attenuate motor deterioration in subjects with early Parkinson’s disease versus placebo20. There are also ongoing clinical trials evaluating the effects of semaglutide as a treatment option in Alzheimer’s disease and Parkinson’s disease21. Such observations pave the way for further exploration of GLP-1 analogues in the prevention and management of age-related cognitive impairment and neurodegenerative disorders.
Reducing morbidity and extending healthspan
In addition to their cellular and molecular effects, GLP-1 analogues may contribute to reduced morbidity, a key concept in longevity research. By targeting obesity and its associated comorbidities, these molecules could potentially delay the onset of age-related diseases and disorders such as arthritis, hypertension and diabetes, allowing individuals to spend more years in good health. Intentional weight loss, particularly using GLP-1 analogues, has been shown to modulate cellular ageing processes23, reduce the risk of chronic diseases, preserve physical function, and potentially impact longevity24. However, it should also be appreciated that data regarding the long-term effects of
GLP-1 analogues is scant and current recommendations suggest only up to 2 years of therapy. Consequently, pharmacologically assisted weight loss should also be complemented with lifestyle modifications. Indeed, physical activity and lifestyle behavioural change should potentiate the benefits of GLP-1 analogues in the context of longevity. We await data relating to GLP-1 analogues and a well-appreciated surrogate marker of biological ageing, such as epigenetic clocks25.
While further research is warranted to elucidate the specific mechanisms and translate these findings into clinical applications, the emerging evidence highlights the promising potential of GLP-1 analogues in the quest for healthspan extension and the pursuit of longevity.
Conclusion
While further research is warranted to elucidate the specific mechanisms and translate these findings into clinical applications, the emerging evidence highlights the promising potential of GLP-1 analogues in the quest for healthspan extension and the pursuit of longevity. By targeting multiple aspects of ageing, including cellular senescence, inflammation, cognitive function, telomere length and obesity-related comorbidities, these molecules may offer a multifaceted approach to promoting healthy ageing and potentially extending lifespan.
Figure 1 Adapted from Kalra, S., Das, AK, Sahay, RK, et al. Consensus Recommendations on GLP-1 RA Use in the Management of Type 2 Diabetes Mellitus: South Asian Task Force. Diabetes Ther 10, 1645–1717 (2019).
