A longevity chronicle: The development of anti-aging pill

With the buzz of Metformin under trial for being a first anti-ageing medicine, we review this exciting phase of ‘anti-aging’ research and hurdles in developing the panacea of all the mortal ills.

By Ajay V. Patil

Anti-aging researcher Dr. David Sinclair quoted – “the first person who will live 250 years is already born”. But is it possible to push the boundaries of what is perceived as ‘maximum healthy life span’ in the coming future? Addressing the conundrum of, whether aging itself is a physiological or pathological process will probably give solutions to other age related diseases like cancers, cardiovascular diseases and dementia.

Targeting aging as a pathology – Fixing ‘cure a disease at a time’ approach

Aging research often evoke the thought of eternal life. But in practicality what researchers are trying to achieve is not eternal life, but ‘extension of healthy life span’. Attempts to get closer to this goal by researchers mostly involve seeking solutions to individual aging disabilities. However, current notion suggests that, acknowledging aging itself as a final pathology will ultimately address the quest for comprehensive therapy. In various animal models, from yeast to fruit fly to mice, researchers could extend the lifespan to certain extent by tweaking the crucial pathways, using intervention strategies like, ‘caloric restriction’ (1). Years of research revealed important signaling pathways and crucial players of this process like Sirtuins, IGF and mTOR (2,3). Interestingly such pathways are known to regulate insulin sensitivity and glucose turnover in the body. This was an encouraging and affirming breakthrough, as it aligned well with ‘caloric restriction based life extension model’ validated by numerous research studies over the years.

Caloric restriction (CR) and resveratrol – Initial interventions

Multiple studies showed, extension of lifespan and delayed onset of age related diseases in mouse and other model animals on CR without malnutrition. A recent study also showed that CR is effective in delaying the aging defects in nonhuman primates (4). Early results from CR studies gave the hope for new interventions like, drugs that could slow aging and the appearance of allied diseases. Besides CR, chemicals like resveratrol and metformin are also considered as promising anti-aging reagents.

Resveratrol (3,5,4′-trihydroxystilbene) was first described in 1939 in the extracts of Veratrum grandiflorum. Mechanism of resveratrol activity is through its regulation over a class of proteins called Sirtunins, especially Sirtuin1 (SIRT1). SIRT1 regulates numerous cellular processes like DNA repair, insulin sensitivity, fat differentiation, neurogenesis and fatty acid oxidation. But, lifespan extension by resveratrol in yeast and drosophila showed Sir2 dependence. Distinguished lifespan extension by resveratrol independent of Sir2 activity is debated by conflicting reports. There is no clear understanding of lifespan extension resulting from resveratrol treatment in healthy mammals so far (2).

Metformin and life extension – A learning curve

Metformin was first clinically approved in 1972 as anti-diabetic drug in Canada. It also works as anti-aging drug by increasing insulin sensitivity and consequently causing decreased IGF-1 signaling, inhibition of mTOR and reduction of endogenous production of reactive oxygen species (ROS). It also activates AMP-activated kinase (AMPK), and reduces DNA damage. Thus, it positively modulates metabolic processes crucially associated with ageing conditions like inflammation. Apart from this, some studies showed that metformin can delay aging and increase healthy lifespan in model animals, when fed in the diet (5,6).

Targeting Aging With Metformin (TAME) – Clinical trial for human life extension

In human subjects, metformin treatment showed reduced incidence of type II diabetes mellitus, improvement in cardiovascular disease factors and subclinical atherosclerosis. It showed, 20% risk reduction for cardiovascular diseases and 42% risk reduction for diabetes-related deaths.

After getting insights from previous metformin disease response data and few clinical trials, American Federation of Aging Research (AFAR) is sponsoring a comprehensive clinical trial, TAME, to correctly measure time to a new occurrence of cardiovascular events, cancer, dementia and mortality under metformin treatment. The trial will evaluate around 3,000 subjects, between ages 65–79, across 14 centers in the U.S.A. Outcomes from this trial are expected to benefit ‘direct targeting of aging’ instead of ‘a disease at a time’ approach (3).

Commercial interest and future

Beyond the academic research and clinical studies, there is also considerable commercial interest in aging research. Companies like Calico, Human Longevity Inc. have raised significant funds and secured tie ups with major pharma players (7). Probable research direction for these companies is – to develop comprehensive databases on human genotypes and phenotypes, and then use machine learning approaches to develop new ways to fight aging related diseases.

With advances in sequencing technology, understanding of interconnections between important endogenous factors such as stress levels, sleep deprivation, insulin sensitivity, microbiome consistency is clear. This knowledge is currently being translated to target many age related diseases individually with limited success. But in the future, we hope to see simultaneous modulation of diet, lifestyle and chemical interventions to extend healthy lifespan.

Reference

1. Fontana et al., Science; 2010
2. Bhullar et al., Biochimica et Biophysica Acta; 2015
3. Barzilai et al., Cell Metabolism; 2016
4. Pifferi et al., Communications Biology (Nature); 2018
5. Anisimov et al., Cell Cycle; 2008
6. De Haes et al., PNAS; 2014
7. de Magalhaes et al., Trends Biothechnol., 2017

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