Pharmacology to Target the Mechanisms of Aging is a Going Concern

Traditional pharmacological drug development involves (a) identifying a protein or protein interaction of interest in the body, (b) screening the small molecule libraries for a compound that affects that target, and then (c) making a better version of that small molecule: more effective, less harmful. That remains the bulk of the medical research and development industry, despite the proliferation of other approaches, including cell therapies, gene therapies, recombinant proteins, monoclonal antibodies, and so forth. There are goals that cannot be achieved by small molecules, and, as techniques improve and costs fall, gene therapies of various sorts will ultimately replace a great many small molecule therapies.

That is yet to come, however, and thus much of the first wave of the longevity industry is focused on turning out small molecule drugs that can in some way influence mechanisms of aging. This can be very promising, as in the case of senolytic drugs that cause senescent cells to self-destruct, or it can be likely of only modest benefit, as in the case of mTOR inhibitors that provoke cells into greater stress response activity. All too much of the work taking place today is of the latter category, and will probably provide, at best, similar gains in long term health and life span to those that can be achieved by exercise or the practice of calorie restriction. If we want to truly change the shape of a human life, more than this is needed.

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. 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 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-19, 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.

Link: https://www.lifespan.io/news/longevity-pharmacology-comes-of-age/

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