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Aging as a Target is a New Therapeutic Frontier


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Posted 27 August 2020 - 07:37 PM


My attention was recently drawn to an open access commentary on the present early stage of the scientific initiative to treat aging as a medical condition. It was published earlier this year, and slipped past my notice amidst all of the other interesting papers emerging at the time. It is illustrative of a number of similar commentaries, in scientific journals, at conferences, and so forth, and is reflective of the present tenor of discussion among researchers. The scientific community is largely optimistic about the potential to intervene in the aging process, even if opinions vary widely as to how hard it will be, from a technical perspective, how much of a benefit to health and life span we can expect to engineer over the next few decades, and how much of a roadblock to progress is presented present systems of regulation, none of which yet recognize aging as a legitimate target for medical development.

We live in interesting times, witnessing the emergence of a new and very important field of scientific endeavor, concurrent with the emergence of a new and energetic medical industry of longevity, a period in which previously small scientific and advocacy communities blossom into large and earnest movements that overtake and transform existing institutions. The last five years and the next five years are a tipping point in the slow, decades-long cycles of business and technology, the prior phase of ineffective approaches to the diseases of aging giving way to and era of new biotechnologies and new approaches that will ensure longer, healthier lives for all. To my eyes that transformation is best explained as a shift to targeting the causes of aging, to repair the underlying damage to cells and tissues, rather than trying to treat the symptoms of aging caused by that damage. The next hundred years of medical development will be the focused on the control and reversal of aging; longevity assurance will be the defining industry of the 21st century, ultimately larger than all of the rest of medicine put together.

Aging: therapeutics for a healthy future

Many consider aging as a purely chronological phenomenon; it is an immutable fact that we all get older. However, this is a simplification as individuals all age functionally in different ways and the concept of "biological aging" is more relevant than chronological aging. When we consider biological aging, we have a therapeutic target, not simply targeting getting old, rather treating physiological decline that is manifested by dysfunction and morbidity in late life.

When biological aging becomes pathological, it can be considered as a failure of homeostasis. There is a progressive component, but ultimately a point is reached at which there is inability to counter the amassed toll on the body of time-dependent accumulation of cellular damage (DNA mutations, protein misfolding, oxidative stress, etc.), which occurs throughout life. With age, cellular processes (including stress response pathways invoked by damage) become less efficient, ultimately leading to cellular death and irreversible consequences. At younger ages, the body is able to mount compensatory responses and life is healthy. During middle age, the body's ability to maintain homeostasis declines, resulting in chronic diseases that accelerate the gradual degradation of life quality, resulting in severe detriments, frailty and, eventually, mortality. There are many ways that a homeostatic balance can be maintained, giving many opportunities for development of therapeutics.

Development of drugs in recent years has focused almost entirely on selectivity and specificity with a primary goal to reduce the risks of any side effects. Such an approach is highly valid when considering specific indications targeting selected organs. Aging is different; the body ages systemically, although not necessarily uniformly, and it may indeed be preferential to have broad, systemic anti-aging effects. Consideration of systemic therapies, broadly distributed targets or organ systems that can have wide impacts may be strong and viable strategies to take. Approaches of potential broad value are to modulate processes that are ubiquitous, systemic and that potentially have multiple impacts such as targeting the plasma proteome, cellular senescence, proteostasis, and metabolic processes.

Is a golden bullet of a single drug to impact aging biology a realistic scenario? The diversity of age-related disorders, the multitude of potential endpoints, the complexities of genetic risk factors and environmental challenges accumulating over a lifetime all make a single therapeutic unlikely. However, if there are fundamental underlying mechanisms, such as cellular senescence or failure of proteostatic maintenance, or a natural mixture, such as plasma or a fraction of plasma able to modulate multiple mechanisms, then potentially a single therapeutic could halt, or at least delay, most age-related disorders. It is still early for us to ascertain this, but the prospect will be tested in the clinic.

Regulatory issues pose some hurdles to the development of anti-aging therapeutics, but with a common goal in mind these can be navigated. Firstly, the FDA requires clinical trial endpoints be related to specifically impacting health or quality of life - survival, function, or feeling, not biomarkers. This must be kept in mind as we develop drugs, although biomarkers are going to be critical in assessing efficacy especially over extended time periods, they will not by themselves be sufficient for approval. Secondly, payers require a specific disease code for patient reimbursement, these will need much consideration as we move concepts from targeting specific indications to generalizing age-related diseases. These areas, which can be resolved by working together, should not be left too late for consideration.

We are at an exciting juncture where the realities of anti-aging therapies are upon us, and discussing how we can practically advance such approaches is a necessity. Even though a majority of research and therapeutic development focuses on individual domains such as neuroscience or behavior alone, thinking in the context of a systemic impact as we age provides wholly new opportunities, not only to tackle neurological disorders, but a spectrum of age-related ailments. The involvement of multiple disciplines, perspectives, and constituents in the field will be needed to be successful. This collaborative approach must be triggered so that quality of life for all can be improved in the near future.


View the full article at FightAging




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