Ageing as a therapeutic target

Ageing is one of the biggest causes of human suffering. It results in a functional decline in almost every organ and an increased risk of osteoporosis, arthritis, macular degeneration, hearing loss, diabetes, heart disease, cancer, and many more debilitating conditions. Physiological changes are especially apparent in the brain, where large scale loss of nerve cell structures and synapses in the cerebral cortex, among chemical changes, are thought to contribute to the dramatic decline in learning and memory associated with ageing.¹

Given that ageing is the single greatest risk factor for so many diseases, research into the treatment of ageing itself is critical for the future of human health. This requires an understanding of some of the molecular processes that govern ageing, which largely stem from the ‘Free Radical Theory of Ageing.’² Free radicals are highly unstable molecules with an unpaired electron, which can damage biological molecules. They are formed in the body as natural metabolic by-products, or through exposure to pollution and cigarette smoke. The Free Radical Theory of Ageing suggests that free radical damage, particularly to proteins, builds up in cells and tissues and causes ageing, since certain types of protein damage have been linked to a shorter lifespan.³ The theory is still contentious, since proving whether such damage is a cause or result of ageing is difficult.

To protect against free radical damage, animal cells have intrinsic defences. These include the production of antioxidant enzymes, which neutralise free radicals. Many health products, such as skin creams fortified with the antioxidant vitamin E, have claimed that boosting antioxidant defences has anti-ageing benefits. A landmark study in this area involved a supposed lifespan extension in fruit flies by artificially causing them to overproduce two antioxidant enzymes.⁴ Following publication, the authors realised a flaw in the study design, and published a new paper demonstrating that the artificially-enhanced flies in fact had no lifespan extension compared to normal flies. ⁵ Unfortunately the earlier paper had already bolstered numerous assumptions about the anti-ageing benefits of antioxidants, while numerous studies now suggest that ageing is about much more than free radicals. From a dietary perspective, taking antioxidant supplements has little effect on ageing. This is based on a systematic review and meta-analysis involving 232,606 clinical trial participants and vitamin supplements consisting of vitamin A, E or beta-carotene, which are all antioxidants.⁶

While vitamin supplements may be ineffective as treatments for ageing, there are other dietary changes which could prove beneficial. Some of the most successful interventions to extend lifespan across model organisms from yeast to monkeys have come from dietary restriction, a reduction of nutrient intake without malnutrition. Using dietary restriction, rodent lifespan has been increased by up to 60%.⁷ Diet restriction seems to function as a mild stress that triggers protective mechanisms, and the mode of action is the dampening of certain molecular nutrient-sensing pathways. These pathways detect the levels of various molecules, such as fats, amino acids and sugars that fluctuate with diet, and adjust metabolic responses accordingly. For example, when nutrients are abundant they trigger fat storage, while food scarcity might trigger fat break-down. Mutation to key genes involved in these pathways has extended lifespan of model organisms, and it seems that long-lived humans tend to have beneficial variations of these genes.⁸ Drugs that act to suppress one or more of these pathways, such as rapamycin, have been shown to extend lifespan in animal models,⁹ though rapamycin may also downregulate the immune system.

Another drug which has been used to successfully increase lifespan of model organisms is resveratrol, a natural plant compound found in berries such as grapes and wine. Resveratrol must be concentrated into clinically relevant doses, since it has been estimated that a person would have to consume 1,000 bottles of red wine a day to obtain a therapeutic amount.¹⁰ Despite compelling evidence of lifespan extension in animal models, there have not been any clinical trials of resveratrol as a treatment for ageing in humans. However, resveratrol pills have shown promise in treating Alzheimer’s disease.

In conclusion, several avenues for the treatment of ageing exist, but long-term evidence of their safety and efficacy is lacking. This is likely a result of the necessary length and cost of such trials, and the controversies of treating what most people consider an inevitable natural process. Rather than attempting to stretch lifespan out, researchers of ageing focus on making later years healthier.

References

1. DeKosky, S. T., and N. H. Bass. “Effects of ageing and senile dementia on the microchemical pathology of human cerebral cortex.” Ageing of the brain and dementia. Raven Press, New York (1980): 33-38.
2. Harman, Denham. “Ageing: a theory based on free radical and radiation chemistry.” (1955): 298-300.
3. Clancy, David, and John Birdsall. “Flies, worms and the Free Radical Theory of ageing.” Ageing research reviews 12.1 (2013): 404-412. Somatic DNA damage in Drosophila melanogaster.” Ageing cell 8.3 (2009): 331-338.
4. Orr, William C., and Rajindar S. Sohal. “Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster.” Science 263.5150 (1994): 1128-1130.
5. Orr, William C., and Rajindar S. Sohal. “Does overexpression of Cu, Zn-SOD extend life span in Drosophila melanogaster?.” Experimental gerontology 38.3 (2003): 227-230.
6. Bjelakovic, Goran, et al. “Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.” Jama 297.8 (2007): 842-857.
7. Anderson, Rozalyn M., Dhanansayan Shanmuganayagam, and Richard Weindruch. “Caloric restriction and ageing: studies in mice and monkeys.” Toxicologic pathology 37.1 (2009): 47-51.
8. Bjedov, Ivana, and Linda Partridge. “A longer and healthier life with TOR down-regulation: genetics and drugs.” (2011): 460-465.
9. Bjedov, Ivana, et al. “Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster.” Cell metabolism 11.1 (2010): 35-46.
10. New Scientist Feature Article. 30 November 2016. Good hydrations: Is there a safe level of alcohol? https://www.newscientist.com/article/mg23231020-600-booze-ruse-can-a-drink-now-and-then-really-boost-your-health/