Very few of the presently available interventions for aging are forms of rejuvenation, and of these most are debatable or have small, unreliable effects. Beyond senolytic drugs to clear some fraction of senescent cells from aging tissues, an approach that is producing sizable, reliable effects in animal studies and that will soon enough become a major part of healthcare for the old, other present treatments can only be argued to be forms of rejuvenation. Either they are not addressing root cause damage, or their effect sizes are so marginal as to make it unclear as to whether anything interesting is taking place. Consider photobiomodulation for example, or other forms of laser treatment that might possibly produce benefits via slightly reducing the burden of senescent cells in skin. These are weak indeed in comparison to the effects that should arise from senolytic drugs, assuming the similar levels of clearance of senescent cells are obtained in humans as have been observed in mice.
But where does one find the information that might aid in deciding which treatments are useful versus marginal? The Forever Healthy Foundation is performing a public service by picking some of the more credible of presently available potential interventions in the aging process, a list that does include treatments capable of only small benefits, and conducting a deep review on each. The outcome in each case is a comprehensive risk and benefit assessment that will be of great use to anyone minded to try these interventions in advance of widespread use and the necessary decade or so it takes for anything to work its way through the system of trials.
The Forever Healthy Foundation staff published their first analysis today, covering the presently popular approach of upregulating NAD+ levels in mitochondria in order to turn back some fraction of the age-related decline in mitochondrial function, an important aspect of aging. To the degree that this works, it is not repairing underlying damage; I would say it is more akin to pressing the accelerator harder in a failing engine. Nonetheless, a range of supplements and other approaches exist to accomplish this goal, and a recent small clinical trial suggests that this approach can produce benefits to cardiovascular function in old individuals. The strategy is not free from concerns, however, and the review suggests that younger people should avoid these supplements.
Senolytics, NAD+ restoration, lipid replacement, decalcification, mTOR modulation, geroprotectors ... - the first generation of human rejuvenation therapies is available today. However, the field is still very young and the information often spotty. New therapies are emerging, and existing ones are updated or replaced. Many of us can not or do not want to wait for decades until we have all the knowledge, perfect therapies and a lifetime of experience on how to implement such therapies. To take advantage of this exciting development right now, we need to navigate this time of transition and make very personal decisions about which treatments to apply and when. Arming ourselves with the best knowledge about therapeutic options is vital.
To rise to this challenge, we have created our Rejuvenation Now initiative to: (a) continuously identify potential new rejuvenation therapies; (b) systematically evaluate new and existing therapies on their benefits, risks, procedures and potential application; (c) evaluate providers for specialized therapies (such as stem cell treatments); (d) freely share our evaluations, protocols, and learnings. The initiative is set up as an international collaboration of scientists and doctors in combination with the team we are building at our foundation's headquarters.
This analysis of NAD+ restoration therapy is part of Forever Healthy's Rejuvenation Now initiative that seeks to continuously identify new therapies and systematically evaluate them on their risks, benefits, procedures and potential application. NAD+ is a pyridine nucleotide found in all living cells. It plays an important role in energy metabolism and is a substrate for several enzymes (including those involved in DNA repair). NAD+ levels may decline markedly with age and restoring those levels to a youthful state is believed to have beneficial effects on health and longevity.
Restoration of NAD+ levels has been shown to have beneficial effects on several organ systems and diseases with an excellent acute toxicity profile. The main benefits are in diseases or conditions that threaten the energetic status of the cell such as ischemic stroke, heart failure/infarction, and mitochondrial diseases. The highest level of evidence for NAD+ restoration therapy in humans is for skin diseases. There is a multitude of potential benefits for which the evidence level is still quite low because of the lack of clinical trials.
The major risks are related to tumorigenesis, the buildup of metabolites with undesirable effects, and an increase in the proinflammatory senescence-associated secretory phenotype of senescent cells. These have not appeared in clinical trials to date but have been identified during mammalian preclinical trials. More clinical trials are necessary to adequately assess the risk of long term NAD+ supplementation. Short and medium-term supplementation (up to twelve weeks) with NR elevates NAD+ levels safely and effectively but there is a lack of studies examining the potential adverse health effects of chronic, year-long NAD+ supplementation.