Is the Fountain of Youth a Metabolite Away?

The media touts a new stay-young regimen every day, such as caloric restriction (equal to starvation for a food lover like me) or the consumption of red wine (a more palatable undertaking). The truth is, aging is astoundingly complex and is influenced by our diet, environment, genetics and the microbiome within us.

by Kirk Beebe

Having just celebrated another birthday, I really started thinking about how to slow my descent “over the hill.” The algorithms driving social media apparently know this, too, as I am frequently served unsolicited ads for “over 40,” “anti-aging,” or “muscle-building supplements.”

Although these advertisements have superficial appeal, as a scientist, I prefer solutions grounded in data. I believe that if we truly understand the details of a biological process, we may be able to derive specific strategies for improving life or health span.

The media touts a new stay-young regimen every day, such as caloric restriction (equal to starvation for a food lover like me) or the consumption of red wine (a more palatable undertaking). The truth is, aging is astoundingly complex and is influenced by our diet, environment, genetics and the microbiome within us.

Science is beginning to lay a pretty compelling trail of breadcrumbs about the processes behind aging, and metabolomics and other clinical and biological measures may forge new paths toward wellness and longevity.

While primary research continues to pour out each month, these “breadcrumbs” are consolidated nicely in several recent reviews. Fontana and colleagues1 focused on the dietary or interventional angles that are emerging, and a review by de Cabo et al2. boldly took a stance on the lifestyle, pharmacological and molecular themes that appear to be the most viable lines of pursuit for aging research. This is precisely the type of information I am looking for in my personal quest to stay young.

If their review was a 10,000-foot view and I elevate that to 30,000 feet, a target becomes clear:  management of nutrients and their metabolism, chiefly by the mitochondria. As the metabolic hub of our cells, mitochondria have been a focus of aging research for decades and are investigated intensely in many age-related diseases such as diabetes, cancer and Alzheimer’s. While this is no surprise to many of you, it is often not well appreciated in our gene-centric life sciences world just how integrated mitochondria are to complex cellular function and fate. Just this spring, Sabatini and colleagues3  described how old and young mitochondria are allocated based on specific properties of the daughter cells upon division of stem-like cells.

But, beyond the mitochondria as a whole, researchers are increasingly identifying specific nutrients or metabolites that have important roles in mitochondrial function and aging – things that in theory could serve as elixirs (i.e. supplements) for antiaging. A mitochondrial metabolite called alpha-ketoglutarate was shown to extend longevity in a model of aging4. Another metabolite, NAD, is frequently cited with ties to nutrient regulation, mitochondrial homeostasis, and aging5.  And, even the most-prescribed diabetes drug on the planet that is also a focus of aging research, metformin, was shown to target a mitochondrial enzyme after almost 100 years of clinical use without knowledge of the target6. Finally, “secreted compounds” (likely metabolites) have been described to regulate aging in an animal model7.

Molecules like these offer the seductive possibility that dietary supplements may be a simple solution to repressing the effects of aging. But, after having read numerous reports where diabetes, aging or cancer were reversed in animal models, my commitment to begin such supplementation regimens requires far more validation in humans.

Perhaps the work that Metabolon is doing with newly launched health platforms such as Craig Venter’s Health Nucleus and Lee Hood’s Arivale, which attempt to leverage tools including whole genome sequencing, microbiome analysis and metabolomics to tackle aging-related biological decline, will provide the evidence I seek. I anxiously await the results of these massively ambitious projects before I commit my dollars to a health food store – and potential longevity – to specific supplements.

My bet is that continued investigation into the relationship between the mitochondria and cellular nutrient homeostasis will expose longstanding secrets about aging. In the meantime, I will continue my battle against aging with the basics that nearly everyone agrees are keys to promoting health, if not also longevity:  diet (quality and quantity) combined with regular exercise. And, some red wine…just in case.

For more information see:

1. Fontana, L. & Partridge, L. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106-118 (2015).
2. de Cabo, R., Carmona-Gutierrez, D., Bernier, M., Hall, M.N. & Madeo, F. The search for antiaging interventions: from elixirs to fasting regimens. Cell 157, 1515-1526 (2014).
3. Katajisto, P. et al. Stem cells. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science 348, 340-343 (2015).
4. Chin, R.M. et al. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397-401 (2014).
5. Mouchiroud, L. et al. The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell 154, 430-441 (2013).
6. Madiraju, A.K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542-546 (2014).
7. Maures, T.J. et al. Males shorten the life span of C. elegans hermaphrodites via secreted compounds. Science 343, 541-544 (2014).