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[ed note: Michael Jorrin, who we like to call ”Doc Gumshoe,” is a longtime medical writer who shares his mostly non-investing-related thoughts with the Gumshoe community a couple times a month. You can see all of his columns here.]
Every single health or medicine-related topic in one way or other touches on aging. We know that lots of things we do are bad for us and will likely dispatch us to an early crossing of the river Styx. We know about the dreadful diseases and dangerous activities that boost employment rates in the undertaker community. And, to balance the threats that we all know about, I’m confident that we’re all aware that life spans have increased significantly, not only here in the US, but all over the planet. But, somehow, it’s difficult to derive much comfort from those impersonal numbers.
Life expectancy data is affected in a major way when there are declines in infant mortality. For example, when Cuba created a community health program (after Castro took over), life expectancy went from just over 63 years to more than 79 years – a tiny bit higher than in the US. Most of this was due to a huge reduction in the infant mortality rate – from almost 80 per 1000 live births in 1950 to 5.13 per 1000 by 2010 (in the US, the rate is 5.4 per 1000 live births).
But a decline in infant mortality does not do one single thing for my own life expectancy, or anybody else’s, for that matter.
Similarly, other changes that have boosted life expectancy don’t affect my own chances of making it to the century mark. I already don’t smoke – never did! – and I always wear my seat belt. There’s not a lot of gang activity in my quiet town, and when my neighbor goes hunting, he does it with a bow and arrow (really!).
When we read about people surviving past the age of 100, we can’t help wondering whether they did anything particular to contribute to their longevity. A couple of weeks ago I read the front-page obituary in the NYTimes of an Englishman named Nicholas Winton, who had rescued 669 mostly Jewish children from Nazi-occupied Czechoslovakia in 1939. He died on July 1st, at the age of 106.
And then there was the excellent Swiss tenor, Hugues Cuénod, who died in the year 2010 at the age of 108. He didn’t have a big voice – it was light, agile, lyrical, and lustrous. He mostly sang early music, not much later than Bach, But he did make his Metropolitan Opera debut as the Emperor Altoum in Puccini’s Turandot – at the age of 84. He gave his last recital at the age of 90, and entered into a civil union with his life-long partner at the age of 106.
What about Jeanne Calment, in Arles, France, who was still riding a bike when she reached her 100th birthday. As a young girl, she had sold art supplies to Vincent Van Gogh. For her 120th birthday celebration, she dined on foie gras and chocolate. She died on August 5th, 1997, at the age of 122.
Did these folks – and the many others whose lives did not include deeds worthy of obits in major newspapers, but who survived well past their centennials – do anything particular to extend their lives? Was it luck, genes, or something else?
A clue might come from the prevalence of centenarians in various countries. In the US, according to the 2010 census, we had 53,364. That works out to 17.3 per 100,000 population. Not bad – the global prevalence of centenarians is 4.4 per 100,000. But not so great, either – most European nations do a bit better, and France, with 36.5 centenarians per 100,000, has double our prevalence rate. The Japanese are the champions, with 42.76 centenarians per 100,000 population. These numbers are all predicted to zoom up; for example, in the UK it has been estimated that about one-third of the babies born in 2013 will live to the age of 100.
So, what accounts for this? Is it the French diet of foie gras and chocolate, washed down with plenty of wine? Or maybe the Japanese diet of sushi and tofu?
There are those who say that, in fact, chocolate does have something to do with it. After all, Hugues Cuénod was Swiss – they eat a lot of chocolate, don’t they? So let’s take a quick look at some of the foods and dietary supplements that are proclaimed as retarding aging and promoting longevity. And, taking an optimistic view, let’s start with chocolate.
Health benefits of chocolate – real or hyped?
There’s a good deal of serious clinical interest in the potential benefits of dark chocolate. Clinical trials are under way to evaluate the benefits of dark chocolate on a number of factors or diseases – hypertension, heart failure, Parkinson’s disease, insulin sensitivity, and platelet function, among others. There’s some reasonably good clinical evidence that dark chocolate improved endothelial function and blood pressure, decreased insulin resistance, and lowered serum cholesterol. But there’s a catch. The clinical trials as well as the published data are careful to stress that the chocolate is rich in polyphenols and flavonols. What we’re talking about here is not – repeat, NOT – a slice of chocolate cake after a satisfying dinner, nor yet a hot fudge sundae. Sorry. Most of the reports were clear that the chocolate was dark, low in sugar, or, in some cases, totally sugar free. And the chocolate was consumed “in conjunction with a healthy diet.” Some reports went so far as to acknowledge that the sugar content in some chocolate offsets the benefit.
But I picked chocolate as a point of departure for a reason. It’s the perfect tempting dangling treat to put out as bait to get people hooked with a “healthful” diet plan. Who wouldn’t be tempted to sign on to a plan that claims to address health conditions affecting millions, that promises that you can eat chocolate, and, guess what, it’s good for you? I’m not saying that these plans are all fraudulent. I am questioning, however, when it comes down to implementation, how well they will work.
Coffee is better!
As far as I can tell, no healthful diet plan tells people that they ought to drink more coffee. But, with regard to coffee, the data are very robust. A meta-analysis published in 2014 reviewing 36 studies in more than 1.2 million participants found that persons who drank three to five cups of coffee per day had the lowest risk of cardiovascular disease, while people who drank more than five cups per day were at the same level or risk as coffee abstainers. That meta-analysis confirmed an earlier one, in about half a million participants, which found that coffee consumption of two to six cups per day was associated with the lowest risk of stroke. And that relationship holds true for a number of other diseases – type 2 diabetes, breast cancer, liver cancer, and perhaps Parkinson’s disease and Alzheimer’s disease. By the way, we’re talking about coffee here – not coffee-flavored beverages like a Venti Caramel Mocha Frappucino from McStarbucks.
Will this information help me – or anyone else, for that matter – live a longer, healthier life? I doubt it. I’m already a coffee drinker, and so are most people I know. And I doubt whether people who don’t drink coffee are going to take up that habit on the basis of those data.
Another kind of hook
Recently, one of our fellow denizens of Gumshoe Republic sent me a link to a website that promised five easy steps that would definitively solve all our health issues. He asked me whether there might be anything at all to it, or whether – as usual – it was pure baloney (not his word – he might have said “malarkey”).
Because of my nasty suspicious nature, I mostly don’t take the bait when I see these come-ons. When I watch these interminable repetitive condescending video presentations, usually with the sound off, my gorge rises along with my ire, and I don’t have a good time. But I did watch this one, mostly because I had an inkling of where it was going. Here’s the gist:
At the root of many or most of our health issues is that we are exterminating our intestinal flora – the hundred trillion micro-organisms that inhabit our bodies, mostly in our gut. We do this by doing terrible things like using antibiotics and consuming an unhealthy diet.
The five easy things to remedy this disaster were:
- One: eat only fermented foods, including several fermented milk products, fermented vegetables, etc. (For some reason, this did not include beer.)
- Two: omit from the diet all sugar, foods containing sugar (including sweet fruits), and artificial sweeteners.
- Three: go on a 100% organic diet.
- Four: take probiotic supplements containing those beneficial organisms.
But, unfortunately, they go on to tell us, those first four easy things probably won’t work. Why?
- First, because most people find that fermented foods are yucky.
- Second, because most people can’t stay away from sweet foods.
- Third, because a 100% organic diet is killingly expensive.
- Fourth, because most probiotic supplements consist of organisms that have perished while in the little bottles, so they won’t do you any good.
So the conclusion is, take the probiotic supplement that you can trust, consisting of only live, healthy organisms, from the one single honest trustworthy probiotic supplement maker that you can totally rely on to preserve your life and health.
As with many of these pitches, this one contains its germ of truth. We do indeed carry around a huge number of micro-organisms in our intestinal tract – the number 100 trillion is frequently cited – and these tiny creatures do maintain an important balance in the war against potentially harmful invaders. It’s well-known that a number of GI infections, including the notorious Clostridium difficile (C. diff), emerge when our intestinal flora are adversely affected by a course of antibiotics. An interesting development along those lines is that C. diff is sometimes successfully treated by what is politely termed a “fecal transplant,” consisting of the insertion of donor feces into the intestinal tract. Fecal transplants have also successfully treated Crohn’s disease, and are being studied for other possible uses.
Returning to the proposition that a probiotic supplement can solve most of our health issues, as promised in the spiel I watched – would that it were so. Alas, I fear not. It might help prevent some GI ailments, but that’s about it.
Avoiding disease as the path to longevity
Doc Gumshoe does not usually disagree with the obvious. It’s obvious that a sure avenue to longevity is avoidance of disease – not just curing the disease, illness, malady, condition, whatever we call it – but preventing it from attacking us. Therefore, the hyperbole around some foods and supplements, presented to us as possessing the near-miraculous capacity to prevent – totally, absolutely prevent – a large number of diseases, is highly seductive. Similarly, the dire warnings that there are some foods that we must never under any circumstances consume, are similarly seductive.
One of the foods that we are warned against is wheat. Wheat’s unforgivable sins are numerous. We discussed one of wheat’s sins, the presence of gluten, in the Doc Gumshoe piece on celiac disease. I repeat here what I said then, that unless one is in that one percent of the population that actually has celiac disease, there is little reason to avoid gluten.
But wheat’s cardinal sin is that many food products based on wheat have a high glycemic index, meaning that they are easily and quickly converted into glucose. If two servings of foods have the same number of calories but different glycemic indices, glucose from the food with the higher glycemic index hits your bloodstream faster. It is more difficult for the body’s homeostatic mechanism – i.e., the insulin response – to deal with a glucose load that quickly enters the bloodstream, so foods with a high glycemic index such as refined wheat flour, white rice, potatoes, etc, are considered a risk factor for people with a tendency to diabetes.
Does that mean that strictly avoiding wheat and other foods with a high glycemic index will keep us disease-free and help us survive to the triple digits? I don’t think so. That doesn’t mean that I ignore the significant risk of developing type 2 diabetes affecting practically everyone on our planet. Diet modifications – increasing this, cutting out that – can certainly mitigate risk for many diseases, and thus, as sure as day follows night, can add to life span.
Singling out wheat as an arch-villain is genuinely dopey. The cultivation of wheat, which has been going on since about 7500 BC, was one of the factors that made the development of civilization possible. Wheat is a principal global source of protein – yes, we can refine a lot of the protein out of wheat, as in Wonder Bread. Norman Borlaug was awarded the Nobel Peace Prize in 1970 for his work in developing wheat varieties that resulted in doubling wheat yields in places like India and Pakistan; in Mexico his Green Revolution wheat provided badly-needed protein to the diet of a population whose diet previously relied on corn, a low-protein food. Borlaug is credited with “saving a billion lives” worldwide.
I would say, contrary to internet hype, that wheat definitely has contributed to our longevity as a species.
… but can we figure out how to achieve prevention earlier in the course of disease?
Okay, we know – or think we know – about the things that constitute the Healthy Life Style. Debate about the details will continue despite inspired revelations from all manner of Divine Health Gurus, a society of which Doc Gumshoe is not a member. Let me instead point to a challenge that has been attracting considerable attention from the medical community as well as pharmaceutical companies.
It’s known that many diseases cause significant harm well before they are diagnosed or become clinically evident. In diabetes, irreversible damage can occur in the retina and in the peripheral circulatory system before the patient’s blood glucose levels get near the cut point for defining diabetes. A major problem in Alzheimer’s disease is that by the time the signs of cognitive decline become evident, the changes in the brain have progressed to the point where currently-available treatment options do very little. The debate as to the level at which high blood pressure needs to be treated continues with no resolution in sight. The data linking hypertension with increased cardiovascular risk are irrefutable, but at what systolic BP number does treatment confer a clinical benefit?
A fundamental problem is that clinical studies demonstrating benefit from some form of treatment for most diseases are almost always done in patient populations that are already either affected by those diseases or at clear risk for those diseases. We don’t give Aricept to everyone over age 65 just because that’s the age at which some people start to develop Alzheimer’s, and we don’t – or not yet, anyway – put everyone over age 40 on an antihypertensive drug. We have no idea if some of these treatment options might confer a survival benefit in a patient population that has not been diagnosed with any disease or identified as being at risk.
However, there are hints that, in some areas at least, we may be moving in the direction of preemptive disease prevention – and, along with it, the development of drugs that specifically target aging. It’s hard to draw the line between those two types of drugs, but an important factor is that if a pharmaceutical company were to develop a drug that had no effect whatever on any known disease, but nonetheless blocked or delayed an intrinsic process, it might be extremely difficult to gain regulatory approval for the drug. The FDA and the EMA grant approval to drugs based only on efficacy and safety in treating disease. Fountain of Youth drugs are not their business. But some official agency would need to review the evidence, or we’re right back to the kind of malarkey we were talking about earlier. Therefore, the pharma outfits are likely to present their potentially anti-aging drugs as having a specifically desirable clinical effect, associated with a known disease, which results in prolonging longevity.
Such drugs may exist already.
Metformin – a potential anti-aging drug?
Metformin (Glucophage) is the most commonly prescribed drug for Type 2 diabetes. (T2DM). In the US alone, it’s used by about 50 million people. It works by reducing glucose release from the liver and improving the efficiency of our response to insulin. But it appears to have other effects as well, some of which relate to aging, and not just by reducing the damage from T2DM, but through other mechanisms.
Studies reporting benefits from metformin relating to diseases other than T2DM have been emerging for years. Metformin is now a standard treatment for polycystic ovarian syndrome, and there are also data showing that smokers taking metformin have a lower incidence of lung cancer than the norm. And metformin may also benefit patients with pancreatic cancer.
But the most surprising finding is that metformin may contribute to the health and longevity of individual cells in our bodies through a somewhat paradoxical mechanism. The sources of power in our cells are organelles called mitochondria – and by power, we mean exactly that – an electric current, tiny, but vital. Mitochondria also create adenosine triphosphate, or ATP, which is an energy source throughout the body. Cells have varying numbers of mitochondria; liver cells may have up to 2000,
In the process of producing those tiny bursts of electricity, mitochondria also release tiny burst of reactive oxygen – (O, not O2) – which, in larger quantities are linked to oxidative stress, to combat which health-minded folks eat a lot of blueberries and drink pomegranate juice. But those tiny bursts of reactive oxygen within the cells appear to be highly beneficial to their health. And metformin boosts the activity of the mitochondria, contributing to cell health and survival.
A couple of animal studies support the premise that metformin may be an anti-aging drug. One, in mice, found that mice given metformin have a life-span about 6% greater than those not given metformin. Another, in roundworms (which have a three-week lifespan) demonstrated that the worms who got metformin stayed sleek and plump for longer than the non-metformin worms, which got wrinkly, shrank, and died off sooner.
But the study that points to a longevity benefit in humans was initially meant to investigate why diabetic patients treated with sulfonylureas (glimepiride, glyburide, glipizide, etc) have a higher risk of cardiovascular disease and death than those treated with metformin. The study compared 78,241 metformin patients, and 12,222 sulfonylurea patients with 90,463 matched patients without diabetes, observed for about three years on average.
As expected, patients treated with sulfonylureas had markedly lower median survival rates than did those receiving metformin, by a margin of 38%.
The surprise is that the non-diabetic patients had a 15% lower survival time than diabetic patients treated with metformin, suggesting that metformin may eventually be shown to have a survival benefit in the general non-diabetic population as well as in diabetics. The study was published in Diabetes, Obesity, and Metabolism (CA Bannister et al, November 2014).
However, that study is far from establishing that metformin can be prescribed to the general population as a longevity drug. Even though the study followed a large number of patients (more than 180,000) the total follow-up time was relatively short (less than 3 years), which, for a study assessing survival is not very long. The mean age of the participants taking metformin and their matched controls was a bit over 60 years, and in this cohort the number of deaths was fairly small – 654 in the metformin group and 713 non-diabetic controls. I don’t think this data, interesting and suggestive as it is, will be enough to persuade the regulatory authorities to approve metformin as a general anti-aging drug. But I wouldn’t be surprised to see a lot of off-label use as the word gets out.
However, metformin is far from the only candidate.
Rapamycin might just possibly slow down cellular aging
Rapamycin is a bacteria-derived drug that is FDA-approvcd to prevent rejection of some organ transplants and also to coat cardiac stents to prevent dangerous reactions. Its essential mechanism is to dial down immune responses. But it has a curious and potentially hugely beneficial activity on a cellular pathway that regulates cell growth and division, and, as a direct consequence, cell aging. When this pathway is deactivated, cells shift into a sort of conservation mode – they need fewer nutrients, subsisting instead by recycling old proteins. The process is called “autophagy,” and it’s thought that one reason that in some animals caloric restriction increases lifespan is that autophagy slows down the aging process.
The cellular pathway affected by rapamycin has been labeled “mTOR,” for mechanistic target of rapacmycin, and rapamycin has been demonstrated to extend the lifespan of mice substantially – by about 9% in male mice and 15% in female mice who were started on the drug at a point about two-thirds of the way through the normal mouse life span. Translated into human life expectancy, that might mean somewhere around ten more years on Planet Earth.
A drawback: since the fundamental mechanism of rapamycin is to diminish the immune response, giving healthy patients rapamycin purely as a longevity drug would likely have the undesirable effect of making those Fountain of Youth seekers more susceptible to some diseases, which are no joking matter.
However, there are glimmers – at least! – of hope. Everolimus is a derivative of rapamycin, and given in small doses, it extends the efficacy of flu vaccine in elderly subjects. It’s an mTOR inhibitor, as is rapamycin, but at low doses it appears to modulate immune responses in a beneficial manner. Everolimus is marketed by Novartis as Affinitor for cancer treatment, and as Zortress in the US, and Certican in Europe, to prevent rejection of transplants. Novartis appears to be willing to expend considerable sums on research with everolimus as it relates to the effects of aging. The research will focus on identifying specific physiologic mechanisms linked with aging and search for ways of addressing these mechanisms. It’s not a search for the Elixir of Youth, but for the individual processes that result in aging – discovering what drives these processes and trying to reverse them. For example, in mice – just in mice, not in humans! – rapamycin reduced bone loss as the mice aged, and reversed chronic inflammation and cardiac aging. It also reduced the deposition of amyloid plaque in mouse brains, suggesting that it might be effective in delaying Alzheimer’s disease.
Novartis isn’t the only pharma company that’s betting on aging research. In September 2014, Google and AbbVie put up $750 million to kick off aging research, funding an outfit called Calico – short for California Life Company. Calico has a couple of very preliminary leads that they’re following up. I’m not prepared to guess as to whether they are highly promising or blind alleys – likely somewhere in between.
What about telomerases and DNA replication?
When cells divide, each new cell – “daughter” cells, as they are known – has to have a complete copy of the mother cell’s DNA. This is accomplished by splitting the DNA strands neatly and effectively, so that each daughter cell gets one complete strand, which is copied in the new cell. At the ends of chromosomes, the DNA strands have nucleic acid sequences called telomeres, which convey no genetic information, but serve a vital purpose, which is to protect the integrity of the vital part of the DNA during the splitting process. Each cell division results in the loss of some of the telomeres from the ends of the DNA strands, such that newborns have perhaps five times the number of telomeres as elderly folks. But at certain point in cell division, there are not enough telomeres at the ends of the strands to protect the part of the DNA that codes the genetic information, so the splitting process damages that part of the DNA strand. The cell division process peters out – cells die and are not replaced by new cells.
This happens in almost all of our body’s cells, except in cells vital to reproduction of a species, such as sperm cells and egg cells. In those cells, telomeres are protected by enzymes called telomerases, which prompt the cell to make new telomeres to protect the DNA strands. Thus, telomerases are crucial to the survival of genetic information and new cell creation. (Of course, the body has other ways of discontinuing the production of sperm cells and egg cells, regardless of the presence of telomerases.)
Another type of cells are supplied with telomerases: cancer cells. That’s why cancer cells are able to continue to divide and multiply indefinitely. Thus, telomerases have become a promising target for cancer therapy: inactivate the telomerase in cancer cells, and the cancer will die out on its own. An agent that has shown promise in that approach is imetelstat, from the biotech company Geron, which did much of the basic research into the role telomerase in cancer. The 2009 Nobel Prize for Physiology or Medicine was awarded to two Geron collaborators, Elizabeth H. Blackburn and Carol W. Greider, along with Jack W. Szostak for the discovery of how chromosomes are protected by telomeres and the discovery of the enzyme telomerase.
But what if telomerase could be mobilized to protect the division of all our cells? That could conceivably provide a major boost to our life expectancy. There are a number of hints that it might be possible to put telomerases to work as longevity agent. For example, it has been reported that one of the many effects of the Mediterranean diet is that people following that diet have longer telomeres, which may in some way account for the benefits that have been observed with the Mediterranean diet.
And there are other promising developments. One application of that mechanism that has already been successfully used is in cultured human cells. Muscle and skin cells are treated with modified messenger RNA which contains the coding sequence for telomerase reverse transcriptase (TERT), the active ingredient in telomerase. Three applications of TERT increased the length of telomeres by about 1,000 neucleotides, resulting in up to 40 more cell divisions in some cell types. In the human cell cultures, the result was that, rather than diminishing and dying in the Petri dishes, there was a ten-fold increase in cell populations. This is thought to be equivalent to several years of human life extension.
A clinical use may be in Duchenne muscular dystrophy (DMD), an uncommon genetic disease that affects about 1 in 3,500 boys and results in their early death, usually in the mid-20s. Boys with DMD have much shorter telomeres than unaffected boys, and this deficiency may contribute to the early muscle wasting that characterizes the disease. Scientists at Stanford University are investigating telomerases for treatment of DMD, and perhaps other diseases such as cardiac diseases and diabetes.
But countering the harmful consequences of shortened telomeres in boys with DMS is a far cry from coming up with a formula for extending the lifeline of people with no particular disease other than that endemic condition known as aging. While it’s certainly possible that a strategy similar to the one envisioned for boys with DMD would give me, say, a 10% lifespan increase, instituting that strategy would have to be weighed against the possibility that the telomere extension would also apply to any cancer cells wandering about in my body. It might boil down to a bet.
We looked at three possible mechanisms to slow aging at a fundamental level – mechanisms that are not related to curing or preventing a particular disease, but that affect aging processes that are independent of disease: one, a way of inducing mitochondria to release small bursts of energy in a way that seem to result in increased life spans; two, a way of slowing down cell aging while supporting immune responses; and, three, perhaps a way to protect the telomeres at the ends of DNA strands so that cells can survive more divisions. None of these are likely to provide anything but incremental increases to longevity, and it is possible that none of them will pan out. However, the attention of researchers is increasingly turning to increasing life span. Personally, I’m modestly optimistic. If someone handed me the chance at an additional ten years – ten healthy years! – I wouldn’t say no.
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A few months ago the Alzheimer’s disease “breaking news” was that 99.5% of AD drug trials failed to meet their objectives. I thought then that the interpretation was a bit on the pessimistic side, and their certainly haven’t been any headline-grabbing breakthroughs since then, but there have been some – a few – positive developments since the last time Doc Gumshoe looked at Alzheimer’s in 2013. So I thought I would sleuth around and see what’s been happening in that extremely difficult area. Or if there are other topics that you’re interested in, please let me know. Best to all, Michael Jorrin (aka Doc Gumshoe)
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