A bold feature article published in Drug Discovery Today illustrates the coming of age of longevity pharmacology.
Dr. João Pedro de Magalhães, one of the biggest names in longevity research, outlined some of the great strides taken in the last two decades, as various discoveries have been made in the biology of aging. Lifespan has been manipulated in model organisms via genetic, dietary, behavioral, and, most recently, pharmacological interventions. The potential commercial and societal value is truly astronomical if these findings can be successfully translated into humans, and evidence is building that they someday will.
The field of longevity pharmacology is growing
The number of compounds that have been shown to increase longevity in preclinical models is growing exponentially: it was approximately 300 in 2005, 1300 in 2015, and most recently to 2000 in 2020. Meanwhile, the discovery of longevity-associated genes has plateaued, following an exponential growth until approximately 2010 before transitioning to a slower growth over the last decade. Dr. Magalhães believes that there are probably many more longevity genes left, but the incentives for their discovery are reduced since most newly discovered genes now tend to eventually lead towards already known pathways.
The number of longevity companies has also doubtlessly increased dramatically, although this is harder to subjectively measure, as it is difficult to define what makes a company longevity-focused. Most of these companies deal with the hallmarks of aging, most notably oxidative stress and mitochondrial dysfunction, cellular senescence, and pathways implicated in caloric restriction, such as mTOR. The acquisition of longevity companies by big pharma, for example the purchase of Alkahest by Grifols, is also just beginning to occur. One concern, Dr. Magalhães notes, is the lack of strategic diversity. It is possible that too much weight is being put on these areas despite the much broader range of potential strategies.
Recently, the field has also seen its first clinical failures, a notable rite of passage for all new fields of medicine. In 2019, ResTORbio’s mTOR inhibitor RTB101 failed its Phase 3 trial for a lung disease, and Unity Biotechnology’s senolytic UBX0101 failed to meet its endpoints in osteoarthritis just last year. A myriad of challenges can complicate translation, such as a lack of genetic diversity in preclinical models, pathways that are not conserved between species, and the selection of proper primary endpoints. However, the list of ongoing clinical trials is constantly growing, with active studies including COVID, macular degeneration, frailty, and neurodegenerative diseases. The TAME trial of metformin represents a pivotal proof-of-concept study, which may pave the way for future therapies aiming to broadly target longevity in their applications to the FDA rather than any specific disease. Interest has also been growing in off-label prescriptions and nutritional supplements.
There has also been a ramping up of computer-based methods being applied to the field of longevity. Bioinformatics, machine learning and artificial intelligence, -omics approaches, and large public databases are just beginning to be fully utilized. These techniques may someday improve our abilities to predict the outcomes of clinical trials. They also aim to identify candidate drugs and biomarker and may eventually play a role in the application of personalized, precision medicine.
When taken as a whole, these trends characterize a vibrant, growing longevity industry in its early maturation stage. There are many parallels to the early days of some fields of pharmacology that are now well established, such as cancer and heart disease. While the future is unknown, Dr. Magalhães gives us plenty of reasons for optimism.
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 João Pedro de Magalhães. (2021). Longevity pharmacology comes of age. Drug Discovery Today, in press. https://doi.org/10.1016/j.drudis.2021.02.015