Scientists have used a huge database to find links between existing drugs and human lifespan. Only 14 of more than 400 showed a positive correlation [1].
Reinventing the wheel?
One of the subfields in geroscience was born from the idea that some drugs currently in use for various indications might slow aging. In recent years, we have seen such successes with existing drugs in animal models. For instance, rapamycin, which is mostly used as an immunosuppressant, is one of the strongest pro-longevity interventions in mice.
What about people? Unfortunately, there hasn’t been a single lifespan clinical study in humans. Designing such a trial is difficult due to our species’ remarkable longevity. Hence, our only current option is populational studies of people who take medicines.
One such study had caused a lot of fuss around the anti-diabetes drug metformin, as it showed that diabetes patients who received the drug lived longer than healthy people who did not [2]. Since then, another study has cast those results into doubt [3]. Metformin also failed to increase lifespan in mice in a rigorous trial that was conducted as part of the Interventions Testing Program (ITP).
The fabulous 14
Finally, a large-scale populational study of associations between various drugs and human lifespan is out as a pre-print (that is, it has not been peer-reviewed yet). The authors, which include the renowned geroscientist Alejandro Ocampo, used data from UK Biobank, a huge repository of health data on half a million of British citizens.
UK Biobank contains drug prescriptions for more than 200,000 participants (56 million prescriptions in total). This allowed the researchers to analyze the effects of 406 drugs prescribed to at least 500 patients each. 169 of the drugs had an effect on lifespan. Most were, predictably, associated with shorter lifespan. This is a known phenomenon caused, probably, by the diseases that drugs are prescribed for and by the drugs’ side effects.
However, 14 drugs appeared to positively influence lifespan compared to health-matched controls. The researchers controlled for major factors known to influence lifespan: current smoking status, cancer diagnosis, diabetes, gender, and age at recruitment.
One of the drugs was atorvastatin. This is one of the statins, a class of drugs used to decrease the levels of cholesterol in the blood. Statins have a good safety profile and are generally considered one of modern medicine’s biggest successes. Use of atorvastatin was associated with 9% less mortality risk (hazard ratio of 0.91).
Another winner was naproxen, a non-steroidal anti-inflammatory drug (NSAID) used to ease symptoms of arthritis. It was associated with a 10% decrease in mortality risk. Chronic inflammation is one of the hallmarks of aging and a driver of multiple aging processes. However, we cannot be sure this is the reason for naproxen making the cut. Another anti-inflammatory drug on the list was Otomize, a spray used to treat ear infections with three active ingredients, including steroids.
Something for both sexes
Another well-known drug to be found associated with longer lifespan was sildenafil, also known as Viagra, with a 15% less mortality risk. Again, we do not know the reason. It could be Viagra’s vessel-diluting activity or a case of reverse causation, in which healthier people are more interested in having sex.
Sildenafil, of course, is only prescribed to the male population, but women had their winners too. Those were estrogen-related drugs: Estraderm, Vagifem, estriol, and estradiol. They seemed to have a profound effect, decreasing mortality risk by 33%, 27%, 26%, and 25% respectively. Recent research has shown that menopause and dwindling levels of estrogen associated with it are linked to poorer health, which is improved by hormone replacement therapy (HRT). Interestingly, 17-alpha-estradiol, a “non-feminizing estrogen”, has produced notable life extension in male but not female mice [4].
The three last drugs linked to less mortality risk were the contraceptive Marvelon and two vaccines, Avaxim and Revaxis. The authors specifically note that metformin did not have any effect on lifespan. The study does not mention rapamycin, probably because it is rarely prescribed.
The researchers also looked at classes of drugs. Statins as a class were negatively associated with mortality risk, and even more so were SGLT2 inhibitors, a class of anti-diabetes drugs (36% risk reduction, but in a smaller sample than metformin). The most popular commercial SGLT2 inhibitor is Jardiance (empagliflozin). Another drug of this family, canagliflozin, led to life extension in mice in ITP trials [5].
Populational studies like this one are notoriously hard to interpret and can show correlation but not causation. The researchers controlled for just a handful of confounding variables, and many more factors were probably unaccounted for. However, as the data gets bigger and better, we should see more studies that point to existing drugs as possible geroprotectors.
Literature
[1] Morin, J., Rolland, Y., Bischoff-Ferrari, H. A., Ocampo, A., & Perez, K. (2024). Association between prescription drugs and all-cause mortality risk in the UK population. medRxiv, 2024-03.
[2] Bannister, C. A., Holden, S. E., Jenkins‐Jones, S., Morgan, C. L., Halcox, J. P., Schernthaner, G., … & Currie, C. J. (2014). Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non‐diabetic controls. Diabetes, Obesity and Metabolism, 16(11), 1165-1173.
[3] Stevenson-Hoare, J., Leonenko, G., & Escott-Price, V. (2023). Comparison of long-term effects of metformin on longevity between people with type 2 diabetes and matched non-diabetic controls. BMC Public Health, 23(1), 804.
[4] Harrison, D. E., Strong, R., Reifsnyder, P., Kumar, N., Fernandez, E., Flurkey, K., … & Miller, R. A. (2021). 17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell, 20(5), e13328.
[5] Miller, R. A., Harrison, D. E., Allison, D. B., Bogue, M., Debarba, L., Diaz, V., … & Strong, R. (2020). Canagliflozin extends life span in genetically heterogeneous male but not female mice. JCI insight, 5(21).
