The Fountain of Youth – Part 2

November 14, 2018
Our 2¢ – The Iris Blog

In this segment, I will review some of the supplements and pharmaceutical agents that have generated the most excitement in the anti-aging community. Spoiler alert: some of these appear to work!

First up is resveretrol, that difficult-to-spell and awkward-to-pronounce supplement that has generated a huge amount of attention in the past two decades. Found in grape skins, red wine, and peanuts, some hypothesize that it might be behind the French Paradox – that the French manage to have excellent heart health far beyond what proponents of 1980s-era nutritional recommendations would expect for a people who tend to eat a diet high in animal products and saturated fats. Could it be all that red wine? Personally, I think eating the sorts of delicious, handmade animal products I witnessed in Parisian and Provencal shops would help anyone live longer if only due to the joy they might bring into a non-vegan’s life, but I digress. Is there anything to this resveretrol craze?

Animal and “in vitro” studies (in which cells are studied under a microscope, rather than studying entire living beings) are plentiful. Resveretrol seems to activate an enzyme, sirtuin 1 (SIRT1), which plays a role in multiple pathways in cellular aging. (1)

In mice and simpler organisms, it does seem to extend longevity. In primate studies, it improved some cardiovascular markers including arterial health on monkeys given a poor diet, and was associated with reduced weight gain among lemurs given resveretrol during sedentary periods. While encouraging, by no means were all findings positive.(2)

The list of medications and supplements that inspired a burst of optimism based on in vitro and animal studies is long indeed; the catch is whether high quality human studies will show the same thing. The air began to come out of the resveretrol balloon in 2014, when a well designed study of an elderly population in the Italian Chianti region suggested that dietary resveratrol did not correlate with health or longevity. (3) A proper prospective clinical trial in humans is underway – a one year study on overweight adults checking cardiovascular health and fitness parameters at 75mg and 150mg twice daily -and should have results reported later in 2018. (4) Will resveretrol ever be shown to be a dietary supplement to increase longevity? I suspect not. The recent study data on alcohol use, including red wine consumption specifically, was discouraging; those who drank even a glass a day fared worse in overall mortality than lighter drinkers, and the “two glasses of red wine a day is good for you” crowd (something I advocated until recently) took a major hit, as drinking more than a few drinks a week led to a direct increase in mortality as the drinks per week increased. (5) While it is possible that the concentrated doses of resveretrol found in supplements, or a similar compound like pterostilbene (which has far less human clinical trial evidence on its behalf than resveretrol [6]), might someday show evidence of real benefit in this regard, there is not much compelling science to take these supplements at this point.

For those losing hope that there might indeed be some magic element within a pill that could add years to their life, take heart. For starters, we have one of my very favorite pharmaceutical agents, metformin. It is an old, and effective, diabetes medication that affects cellular metabolism and quite possibly gut bacteria. Like so many of our most useful medications, it is borrowed from Mother Nature, as it was derived in the 1950s from French Lilac, aka Goat’s Rue (how could any plant with two names that good not be worth pursuing in a laboratory?). Metformin binds the signaling protein, AMPK, which affects insulin sensitivity, and limits liver production of glucose. Lab studies have shown a significant survival benefit in worms – around 40%; and the worms not only lived longer, but they appeared more “youthful” – something that must have been fodder for late night talk show jokes (7). More and more studies are showing a decrease in cancer mortality amongst diabetics on metformin versus non-diabetics not taking metformin. The real shocker came in 2014, however, when a huge population-based study from the UK showed that health- and age-matched people without diabetes lived 16% shorter lives than their peers who had diabetes and took metformin (8). Given that having diabetes on your diagnosis list is considered to drop at least 5-10 years off your life expectancy, these results caught the attention of the medical community in a big way!

What is lacking, of course, is a trial that pits age- and health-matched people without diabetes, going forward in time – not looking back through statistics. A randomized controlled trial, the sanctified method by which most physicians prefer to obtain our data, is what’s really needed. It’s expensive, though, to conduct these trials with thousands of volunteers over many years. The FDA has approved such a trial to take place to evaluate the claims for metformin – the “TAME” trial – but whether it will be funded remains to be seen (9). It’s hard to raise tens of millions to study an off-patent drug that costs a few dollars a month.

So, right now, we are left with some promising data, and a few reasons to doubt. A study on non-diabetics with heart disease did not show improvement on their arterial plaques when given metformin (10). Most of us practicing primary care prescribe metformin to scores if not hundreds of diabetic patients, and certainly I have never been struck by any sort of anecdotal “ah-hah” that my metformin patients are doing exceedingly well. So – I am not putting all my patients on metformin, at least not yet. About 10-20% get a persistent diarrhea from the medication, which is a deterrent. A small percentage of people on metformin develop a deficiency in vitamin B12. I also worry about the possible shift in gut bacteria producing unpredictable and untoward effects in my patients without diabetes whose gut bacteria may have been just fine before I started “improving” them. I hope the TAME trial runs; I hope by 2025 we have data from it; and I hope it is overwhelmingly positive. For now, though, I limit metformin use to those with diabetes, but am easily talked into prescribing it for patients with above-normal sugars who are tempted by this tantalizing data.

Last, but hardly least, we come to a drug with the unusual name of Rapamycin. Those of us with some familiarity with Pacific Island geography might rightfully wonder about the “rapa” of the “rapamycin,” and, sure enough, the compound was derived from a bacterium found on Easter Island, known to most Polynesians as “Rapa Nui.” The backstory on the discovery of rapamycin, subsequent loss of interest, and then a great resurgence, is fascinating and outlined in many places. Originally it was thought to have its use as an antifungal agent. Then, researchers realized that it had major effects on cellular metabolism, including an immunosuppressive effect, which led to its approval as one of the medications to be used after kidney transplant under the generic name, Sirolimus. Anticancer properties were then noted, unusual in an immunosuppressive agent, and its cousin medications, such as Everolimus, have been approved for use with breast, kidney and thyroid cancers (11). As study of the substance intensified, it was found to play a critical role in the signaling processes which control a cell’s lifespan, and an entire cellular pathway was named after it – mTOR (mammalian target of rapamycin). You know you’ve made it to the big time when cellular pathways are named after you!

Will it help people live longer, though? It clearly extends mouse lifespans by some 25-30%, and is the first substance with compelling mammalian data in this realm (12). Some express concern that most lab mice die of cancer, due to their unfortunate selective breeding characteristics, so the primary benefit of rapamycin for this population might be its anti-cancer properties. This might not translate so well to us humans, who tend to die of heart disease. However, studies on other animals, such as dogs and monkeys, have suggested improvements in many realms: immunologic, metabolic, and neurologic (13,14). Akin to metformin, Alzheimers researchers are curious about possible preventive properties with rapamycin, given the preserved cognition seen in some of the studies.

What is holding back the adoption of rapamycin is the lack of long-term trials in healthy humans. Given its use as an immunosuppressant, there is concern that it might lead to severe infections. However, using a low dose or intermittent dosing regimens, human studies have shown an acceptably low rate of side effects and lack of issues with unhealthy blood counts (15). The current protocol recommended by those who espouse rapamycin for maximizing longevity, such as Dr Alan Green MD, is to take 6mg once weekly (compared to 5mg daily as a typical immunosuppressive regimen) (16). It still feels early to be writing prescriptions for this purpose. The concerns for side effects gives pause, and the very high cost of an adequately large randomized controlled trial to prove its value as a longevity drug might make it unlikely to ever see such a study – potentially leaving this sort of protocol forever in the “highly experimental” realm. Rapamycin is also a good bit more expensive than metformin, currently in the area of $150/month for the weekly intermittent dosing protocol.

All in all, the world of longevity medicine has not given us anything we can shout from the rooftops about. Good sleep, supportive relationships, healthy diet, regular movement, enjoying life and work – none of these things can be fit into a pill, and they are the cornerstones of a long and happy life, and have copious data to support that they will do more for you than any pill possibly could. The quest for that magic bullet will never end, however, and perhaps we will find that some things can indeed be packed into a pill that can substantially benefit our lives. Stay tuned!

RESOURCES:

1 https://www.nih.gov/news-events/nih-research-matters/how-resveratrol-may-fight-aging

2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903570/

3 https://www.nia.nih.gov/research/announcements/2014/05/resveratrol-does-not-affect-health-longevity-population-study

4 https://clinicaltrials.gov/show/NCT01842399

5 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30134-X/fulltext#sec1

6 https://examine.com/supplements/pterostilbene/

7 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066537/

8 https://www.ncbi.nlm.nih.gov/pubmed/24622715

9 https://www.wired.com/story/this-pill-promises-to-extend-life-for-a-nickel-a-pop/

10 https://www.medscape.com/viewarticle/835676_3

11 https://www.cancer.gov/research/progress/discovery/mtor-inhibitors