The Fountain of Youth – Part 2

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

12 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658445/

13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411365/

14 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207939/

15 http://longevityfacts.com/clinical-trial-anti-aging-rapamycin-healthy-seniors/

16 https://rapamycintherapy.com/

The Fountain of Youth – Part 1

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The notion of a Fountain of Youth – a magical source of a substance any one of us could drink of and slow or even reverse the aging process – has an obvious hold on the psyches of many of us with a few decades under our belt.  We might reasonably assume it is nothing more than myth.  In fact, even the myth of the Fountain of Youth as the object of explorer Ponce De Leon’s desire appears to be nothing more than a tall tale1!  That said, the less desirable aspects of life that often accompany aging – the aches and pains, the slow recovery from a work-out, the chronic diseases – not to mention death itself – ensure that the quest for a Fountain of Youth will never end in the world of medicine.

“Modern medicine” could claim that it is clearly on the right track in this regard.  The average American lived to age 47.3 in 1900; this leapt to 68.2 by 1950.  Much of this remarkable improvement can probably be ascribed to the improvements in infant mortality with better prenatal and obstetric care, immunizations, and public health improvements. Still, American lifespans continued to creep upwards in the ensuing decades, rising to 78.9 by 2010, likely related to improvements in managing cardiovascular events like heart attacks, among other things.  Any smugness we might feel that we are on an inexorable march towards all of us celebrating our 100th birthdays, however, is probably ill-placed.  The past five years have seen a virtual flat-lining of our lifespan.  Even if we go back to 1950, the number of additional years a 65 year old would live was 14 on average; now, 66 years later, that number has only risen five years2.  Given that tobacco use has plummeted since the 1965 Surgeon General’s announcement that, yes, tobacco was bad for us, we might well decide that much of that modest improvement was not due to modern medicine but simply smoking cessation.  The CDC estimates that smoking cuts approximately 10 years off an average lifespan; and the percentage of smoking Americans has dropped from 42% in 1965 to 17% today3; so we might estimate that nearly half of the mortality improvement in the last 50 years is due to the anti-smoking campaign!  Amazing as it seems, if you are a non-smoking 65 year old American, all of the wonderful advances of modern medicine in the past half-century — MRIs and CT scans, robotic surgeries, cardiac cath labs, cancer screening programs, and literally thousands of exciting new drugs — all of this has added maybe two or three years to your life.  That’s it.  It is easy to see why the thirst for a Fountain of Youth still exists.

When studies crop up suggesting that this or that supplement, lifestyle modification, or medication might have a significant effect on our lifespan (or “healthspan” – a new term for adding years before infirmity sets in rather than just counting years lived), the popular press is understandably enthused.  Sorting out just how promising these “breakthroughs” really are can be a challenge.  I will save the discussion of potentially exciting medications and supplements for my next post on the subject.  Let us begin with the most natural of options – changing what we eat.

Since I was in high school, I have been hearing: “the only way to live longer is to restrict calories.”  There is plenty of evidence to this effect, much as it is not nearly as attractive as a sip of magical water. 

Indeed, studies since the 1930s on mice and yeast have showed survival benefit with calorie restriction, sometimes remarkable – in the 40% range. It even has its own acronym in the scientific world – “CR.” That said, many a study has failed to translate from simple organisms, or even rodents, to humans.  Lab rodents are bred to die of cancers; about 80% do so (this fact still pains my mother, who found out the dark truth only as our beloved first, and only, pet rat was dying).  They are also different from humans in many complex and not-so-complex ways.  Therefore, there was great interest in primate studies on calorie restriction, but when finally published, the results have been mixed. The two largest studies, with a 15-30% calorie reduction, have yielded conflicting results. The most recent 23 year study on rhesus monkeys did not show survival benefit, only slight metabolic improvements in young-onset CR (those monkeys who were calorie limited from an early age). The prior study showing marked benefit allowed unlimited food access to controls, while the more recent limited the calorie consumption of its control monkeys to an “average amount” – so perhaps CR has benefit only when compared to unhealthy controls4,5

Finally, someone has tried a human model of this theory, in the “CALERIE” study, a 2 year randomized, controlled study that sought to find out if signs might point to longer life with CR; they had to limit themselves to signs like shifting metabolic rates, because it is hard to find backing for studies that require decades of cooperation, monitoring, and follow-up to really determine if people are living longer.  The study aimed for 25% calorie reduction in 160 normal or mildly overweight individuals (12% ended up being the actual average reduction); neither resting metabolic rate nor body temperature lowered as expected, but modest weight loss, improved blood pressure (only 4%), and better insulin sensitivity were seen. Of note, bone density worsened problematically, further lessening the appeal of the study6.

This would point towards the unattractive conclusion that, while there might be a “fountain of youth” readily accessible if you are a) a smoker; or b) have an unhealthy, over-consuming diet; you might see no remarkable longevity benefit from anything we have discussed if you are already a non-smoker who eats a reasonably healthy diet.

One potential caveat to this is the notion of methionine restriction (you guessed it: “MR”), a relatively new concept.  Methionone, an essential amino acid, meaning we must obtain it from our diet, seems linked to oxidative damage in the mitochondria. Many in the longevity business think that aging is roughly equivalent to the degree of oxidative damage in our cells (rust on metal is a typical oxidative process). Fly, mouse, and rat studies have shown that a 4-5-fold decrease in methionine in diets cause the same benefits as CR; and improve insulin sensitivity beyond just what the fat loss would predict7,8.  Since diabetes – the ultimate end point of poor insulin sensitivity – drops our lifespan by some 6-7 years9, this is doubly of interest.  How do we limit methionine?  Eat less animal muscle10.  All of those healthy proteins some of us have been exhorting our patients to eat to avoid carbs and trans-fats – poultry, fish, lamb, grass-fed beef – are loaded with methionine.  Some in the medical community have responded that eating the WHOLE animal, which is richer in glycine, which gets depleted by high-methionine meals, might limit the apparent damage.  There is also an inherent problem that limiting methionine, also well represented in dairy and eggs, makes it harder to avoid carbs and the inherent risks of insulin resistance from them.  So… the jury is still out.  Moderation is probably wise when it comes to meat muscle; and the now-chic “bone broths” are probably the smartest way to get your meat. 

At this point, I do not see enough evidence to advocate strongly for CR, MR, or any other acronym, when it comes to food restriction, until we learn more.  An individualized diet that stresses whole foods based on your own genetics and health conditions, and lots of vegetables, serves as common sense. And, yes – if you have not quit smoking yet, now is the time!

*Part 2 will address the most promising supplements and pharmaceuticals in the Fountain of Youth realm.*

SOURCES:

1 http://www.nytimes.com/2014/10/26/magazine/my-search-for-the-fountain-of-youth.html?_r=0

2 http://www.cdc.gov/nchs/data/hus/hus15.pdf#015

3 http://www.cdc.gov/tobacco/data_statistics/tables/trends/cig_smoking/

4 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832985/

5 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970791/

6 https://www.nih.gov/news-events/news-releases/nih-study-finds-calorie-restriction-lowers-some-risk-factors-age-related-diseases

7 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755412/

8 ttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049285/

9 http://care.diabetesjournals.org/content/29/1/38

10 http://www.brendadavisrd.com/methionine-restricted-diet/

The Statin Conundrum

The Statin Conundrum

 

One of the most frequently asked questions I get from patients about their medications is:  “Do I really need to be on this statin?”

The answer varies by the patient.  The statin drugs, which are the class of cholesterol lowering medications that end their name with “statin” (i.e., “lovastatin,” “atorvastatin,” etc), are among the most heavily prescribed medications in the world. Once upon a time, in the not so distant past, we in the conventional medical community said things like, “Statins should be in the water supply!”  After all, they reduced cholesterol, overall inflammation, heart attack and stroke risk, and were thought to do nearly no harm — some reversible liver inflammation at times, muscle aches at a rate perhaps no higher than placebo, and not much else.  That perception of statins has changed remarkably in the last five years.  Now, the question is more like: “Do we need them at all?”

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Vitamin D: Miraculous Or Mundane?

Vitamin D: Miraculous or Mundane?

Vitamin D lived a rather humdrum existence until the past decade, shrouded in mystery — there continues a debate as to whether it is really a vitamin or more like a hormone — and largely ignored but for unexciting conversations about bone density, kidney failure and hyperparathyroidism.  Not exactly New York Times lead health page material.  Then, all that changed.  It became possible to test vitamin D levels with a readily available lab test. Studies started coming out suggesting that vitamin D was a key to health.  Physicians were told that some 60-80% of adults were deficient in vitamin D, with D3 levels under the cut-off of 30 ng/ml.  More importantly, these deficiencies were linked to cancer, neurologic disease, immune dysfunction, and heart disease – not just poor bone health.  Large scale screening began, especially among the elderly, and what we doctors found confirmed the studies: most people, even in sunny Hawaii, have suboptimal levels of vitamin D.  But what to do with this information?

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