By David G. Watumull –
While the longevity industry is gaining substantial attention, it faces a unique set of obstacles to its mainstream acceptance by the health care community. A human longevity clinical trial conducted in the traditional FDA manner, even if the Agency classified aging as a disease, would require starting subjects on a longevity treatment modality at least by early middle age (say 35), following them for five or more decades, and then comparing mortality in the placebo group to the treated group.
Conducting such a trial is daunting, if not impossible, for many reasons, including cost, time, and trial design. Who would pay for such a study? How would one control for confounders such as diet, exercise, sleep, and stress over decades? The intellectual property around any longevity treatment modality would expire before the trial was completed!
Acknowledgement of these barriers to the use of traditional clinical design for the development of scientifically credible longevity modalities points to two possible pathways in response. The first, dismiss longevity research as futile and focus on traditional disease-based clinical development. The second: use a combination of longevity animal results with biomarkers associated with aging molecular pathways in humans to define a new set of clinical trial end points that are focused on not just longevity but healthspan, the part of a person’s life during which they are generally in good health.
These changes need to be credible, well-accepted in the scientific and medical community , and supported by an effective regulatory framework. This paper explores the feasibility of option two.
There is strong scientific consensus around the role of chronic, low-grade inflammation in aging (see https://pubmed.ncbi.nlm.nih.gov/37329949/ and https://pubmed.ncbi.nlm.nih.gov/38052484/). An advanced PubMed search using the combination of “inflammation” and “aging” as key words yielded over 30,000 peer-reviewed papers. The term “inflammaging” captures this relationship.
So why hasn’t inflammaging been pursued more often by big pharma? Current big pharma anti-inflammatory drug candidates are typically focused on single molecular targets (cell surface receptors, enzyme antagonists or agonists – think TNF-a, COX2, or IL-23 inhibitors) with inherent side effects that make them undesirable choices to modulate complex longevity pathways or improve healthspan.
A more effective approach would be to focus on developing exceptionally safe molecules with pleiotropic impacts on established inflammaging pathways such as AMPK, NF-kB, mTOR, NRF2, SIRT, etc. as well as effect on animal models of longevity and healthspan.
For example, astaxanthin (Asta), an exceptionally safe marine compound supported by robust toxicity studies, has demonstrated impact on multiple inflammaging pathways and extended lifespan in the National Institute on Aging (NIA, one of the National Institutes of Health) gold standard longevity study, the Interventions Testing Program (see https://link.springer.com/article/10.1007/s11357-023-01011-0). (Full disclosure, I am one of the co-authors of this paper and CEO of Cardax, the Company that supplied the Asta used in this study.) Asta has also extended lifespan in yeast, fruit flies, and worms –well accepted animal models of healthspan and longevity.
Asta is a naturally occurring xanthophyll carotenoid with potent antioxidant activity, broad health applications, and excellent safety. Asta is incorporated into lipoproteins such as LDL, distributed systemically, and incorporated into cellular membranes, where it spans and stabilizes the lipid bilayer and reduces lipid peroxidation. The molecular structure of Asta allows efficient scavenging of free radicals both at the surface and inside of the membrane. Asta localizes in mitochondria and protects against pathological activation of inflammatory pathways such as NF-κB driven by oxidative stress. It has anti-inflammatory properties, showing equivalent efficacy to prednisolone in an animal model.
Asta’s effect on the well validated anti-aging gene FOXO3 is an important example of its pleiotropic impact on longevity and healthspan. FOXO3 is one of only two genes shown to robustly affect human longevity. (https://www.mdpi.com/1660-3397/18/7/351?ref=sanatorium.health)
Importantly, calorie restriction (CR), which is unequivocally considered the best strategy for promoting healthspan and longevity, also robustly activates FOXO3 and blocking the activity of FOXO3 abrogates the longevity-enhancing effect of CR. Astaxanthin “activates” the FOXO3 gene in mice, with the detection of an increase of about 90% of its expression in heart tissue.
Because of the limitations of traditional clinical trial design for healthspan and longevity indications discussed here, the novel FDA regulatory and incentive framework proposed in the THRIVE Act could lead to a paradigm shift in healthcare focused on healthspan propelled by, for example, out the Autoalleviating inflammaging. The Act’s tiered categories and exclusivity provisions would foster investment, lower overall medical costs, and improve U.S. healthspan and longevity and improve U.S. healthspan and longevity.
About the Author
David G. Watumull is Chairman of Lokahi Longevity, LLC, the of CEO, Cardax, Inc., and a Co-Founder AX3 Life, LLC
