Fight Aging!

The big disadvantage of the geroprotective approach to aging, which is essentially to undertake the long-term use of supplements and small molecule drugs to alter metabolism in ways that slow aging over years and decades, is that distinct supplements and small molecules and adjustments tend to combine in unexpected ways. Short of testing every combination in laboratory species, something that Brian Kennedy's team has been working on, one can never know the outcome of combining a treatment. Based on presentations and interviews given by Kennedy in the last few years, the result of combining two geroprotectors that individually modestly slow aging is often instead a modest reduction in healthspan or life span.

This is one of the many reasons as to why I favor the development of therapies to repair the underlying cell and tissue damage of aging, treatments that can be applied once for lasting benefit, and which produce actual rejuvenation, a reversing of the progression of aging. These therapies would not need to be continuously applied, and instead be used very intermittently. We should expect such a repair therapy that targets one form of damage to have little interaction with other repair-based therapies that targeting other forms of damage. Every such therapy should hence provide an incremental benefit. Demonstrating that to be the case is in fact the present focus of the LEV Foundation.

Exercise, or rather the maintenance of physical fitness, is an intervention that modestly slows aging, and, like geroprotectors, an intervention that has to be kept up continuously over time. As it turns out, exercise is subject to the same sorts of issue when combined with geroprotectors as is the case for combinations of those geroprotectors. Some geroprotectors are thought or demonstrated to interfere with the benefits produced by exercise. It is possible that some combinations of exercise and geroprotector produce a net loss rather than a net gain for long-term health. This is food for thought.

Geroprotector drugs and exercise: friends or foes on healthy longevity?

Functional parameters such as cardiorespiratory fitness (CRF), daily steps, gait speed, and skeletal muscle mass, strength, and power predict the risk of morbidity and mortality in humans. Exercise has wide-reaching systemic effects impacting nearly every tissue and intervenes on multiple biological pathways that become impaired with age, including senescence, proteostasis, mitochondrial function/quality, nutrient signaling, DNA damage, and inflammation. Through repeated exercise, these cellular and molecular changes facilitate increasing CRF, muscle mass, strength, and power while also decreasing established risk factors for cardiometabolic diseases and thereby lowering the risk of type 2 diabetes mellitus (T2DM), dementia, Alzheimer's, cardiovascular disease (CVD), atherosclerosis, frailty, and improving cancer survival/remission. Despite extensive research and commercial investment, a pharmacological agent that captures the numerous pleotropic health benefits of exercise has yet to be identified; thus, efforts to increase adherence to regular exercise continues.

Increased adherence to exercise over a lifetime has remarkable health benefits. At the musculoskeletal level, lifelong exercise delays age-related declines in functional metrics while extending a more youthful molecular phenotype later in life. However, with increasing age, sedentary behavior and cardiometabolic risk factors (hyperglycemia, hyperlipidemia, etc.) may contribute to delayed or diminished whole body and skeletal muscle adaptive potential to exercise, which is often referred to as anabolic resistance. Many of the proposed cellular and biological hallmarks of aging are implicated in blunting the responsiveness of skeleteal muscle to a bout of exercise. However, consistent exercise can still elicit robust adaptations in older adults. One year of endurance training can improve CRF by ~ 5 ml kg-1 min-1 in previously untrained 65-year-old or older individuals. Importantly, in healthy individuals, a 3.5-ml kg-1 min-1 greater CRF was associated with a 11% reduction in all-cause mortality.

Intervening on conserved underlying mechanisms of aging before the development of disease could postpone the onset, slow the progression, or perhaps ameliorate multi-morbidity and extend healthy longevity. Numerous dietary, lifestyle, pharmacological, and genetic approaches have identified that lifespan is modifiable in model systems. The mTOR inhibitor rapamycin is the most ubiquitous intervention thus far to extend lifespan in diverse species. The glucose-lowering medications metformin, sodium-glucose transporter 2 inhibitors (SGLT2i), acarbose, senolytics, and estrogenic agonists (17 estradiol) have also been demonstrated to extend lifespan.

Positive results from preclinical models have spurred large-scale public interest in gerotherapeutics, prompting some self-motivated individuals to take one or more putative geroprotective drugs and supplements off-label with the idea of further extending healthy longevity. Several telehealth companies have begun supplying these proposed geroprotectors to thousands of people across the globe. Importantly, it remains unclear whether the benefits of these pharmacologic approaches observed in pre-clinical models or in-patient populations extend to individuals free from overt disease who may also engage in other bona fide health-extending interventions such as exercise. Current dogma suggests combining geroprotectors with concurrent exercise blunts hallmarks of exercise that are associated with healthy longevity. Frequent (daily) dosing of leading geroprotectors blunts clinically relevant improvements to cardiorespiratory fitness, muscle size/strength/power, and insulin sensitivity.