In the press this week
- High-profile, misleading “proof” that aging is inevitable
- Disappointing results from Alkahest trials
- NewYorker article on exercise in a pill
- Splicing factors rescue senescent cells
- Mathematical proof that aging is inevitable
The headlines in the secondary scientific press said
Mathematical models of aging are my specialty, but I’m not foolish enough to believe in the models. I’m skilled and experienced at modeling so that I can adjust the assumptions to make a model do anything I want it to do. I’ve seen time and again how tiny parameter changes can lead to opposite conclusions.
Mathematical models can prove something is possible. “Nature might arrange things in this way…” But math models can never prove something is impossible. Nature always has the option of arranging things in a way that’s different from the assumptions in your model.
In fact, the paper purports to be a general proof that aging is inevitable in all multicelled life. But there are a few animals and many plants that don’t age. Long periods of negative actuarial senescence (during which the probability of death goes down and down for years at a time) are common in trees, molluscs, and sea animals that keep growing without a characteristic, limiting size. Turritopsis and Silphidae are capable of regressing to larval stage when starved and beginning life anew with a full life expectancy in front of them. Annette Baudisch has made a career studying and documenting “negative senescence”. So the idea that aging is some kind of mathematical certainty has about as much credibility as the authoritative declaration in Scientific American that flight by a heavier-than-air craft was impossible (1904 – more than a year after the Wright Brothers’ first flight).
The paper that appeared last week in PNAS is based on the premise that there is a kind of Darwinian competition among cells in the body. Cells reproduce and mutate within the life of an organism. In their model, somatic evolution–genetic change over time among cells in the same body–must navigate a course between Scylla and Charibdis. The result is that mutations must accumulate, leading either to dysfunctional cells, too weak to do their job, or to cancer cells that have lost their allegience to the body and go on
They call this “aging,” but in fact somatic mutations do not contribute significantly to aging [ref]. Rather, in humans, the causes of aging include runaway inflammation, loss of insulin sensitivity, and thymic involution. (In my view, most of these changes are driven in turn by programmatic epigenetic changes in gene expression.) They redefine the term “senescent cells” to mean “cells that lose vigor due to cellular damage”, and then look for somatic mutations that cause the loss of vigor; but in general usage the term usually applies to cells that have critically short telomeres, or have otherwise entered a senescent state through epigenetic changes.
The bottom line is that Masel and Nelson demonstrate a process that theoretically must kill us in the end, but their proof is silent about how long “in the end” might be, and they offer no evidence that the process they describe has to do with aging as humans (or other animals or plants) experience it. Whatever “in the end” might mean, it must certainly be longer than 80,000 years, because that is the age of the Pando Grove which, last time I checked, qualifies as a multicelled life form.
Blowing my stack (forgive me)
No one wants to think that death was handed to us with malice aforethought by evolution/nature/the gods. In African myth, death was an accident caused by the laziness of a canine messenger of the gods. In Judeo-Christian tradition, man would have been immortal if only Adam had not tasted the forbidden fruit. William D Hamilton, one of the most insightful and best-grounded thinkers in evolutionary biology, proved that aging was an inevitable result of natural selection in 1966; forty years on, Baudisch and Vaupel used very similar reasoning to prove the exact opposite–that natural selection could never lead to aging . There are smart, famous people even today who argue that aging derives from the Second Law of Thermodynamics (Hayflick, of all people, is the man who discovered that cell lines run out of telomere).
We want to think that Nature is beneficient, that evolution has done her best by us and made us as strong and durable as possible. If we get old and die, it must be because of something beyond evolution’s control. But it’s just not true. Natural selection first imposed aging on one-celled protozoans, and some of the same mechanisms that cause aging and programmed death in protozoans are active ingredients in human aging today (including telomere shortening and apoptosis). Aging and programmed death have a long evolutionary history, and an ancient genetic basis. We must conclude they exist for a purpose.
William Wordsworth asked, “Who shall regulate with truth the scale of intellectual ranks?”
Winston Churchill told us, “A lie gets halfway around the world before the truth has a chance to get its pants on.”
Arthur C. Clark said, “When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong.”
Young Paul Nelson may be excused for getting carried away by his mathematics, but his mentor (and my former colleague) Joanna Masel ought to know that what they have done is irresponsible. These memes have consequences. Arguably, the small and under-funded community of anti-aging research is the most promising frontier of medical science today, offering a vision that may eclipse multi-billion dollar research programs in cardiovascular disease, cancer and Alzheimer’s disease. Articles like theirs have power because the people who make funding decisions are not experts, they don’t like to be ridiculed, and they’re easily swayed by general sentiment in the research community = people who are already getting the funding.
If we do not correct this impression, it is likely to discredit the most innovative and dynamic field of medical research today.
- Disappointing results from Stanford’s first trials of infusions of young blood
Alkahest is a for-profit spin-off from the Stanford lab of Tony Wyss-Coray, doing research with blood plasma from young animals infused into older animals. I first wrote about the project two years ago. The company leapt ahead of animal studies to try infusions of young plasma as a treatment for human Alzheimer’s patients. Last week, Science Magazine reported on a pre-printed meeting abstract: no change in cognitive trajectory of patients who received the infusions.
The people I know best in the field of young plasma are Irina and Mike Conboy. When I visited them last Spring, Irina told me she expected Wyss-Coray’s protocol couldn’t work. The dosage is not sufficient, the duration of treatment is too short, and (according to the Conboys’ research) it is more important to remove pro-aging factors from old blood than it is to add the factors found in young blood.
Wyss-Coray took a chance, and I wouldn’t want to criticize his ambition. But the research world being what it is, this high-profile failure is likely to set back funding for a promising research field. Let’s do what we can to make sure that research by Wyss-Coray, the Conboys and Amy Wagers continues apace.
- New Yorker touts the Exercise Pill
An article in last week’s New Yorker began with a long encomium to the drug GW501516, developed by GlaxoSmithkline some 20 years ago, sold in the grey market as Cardarine or Endurobol. Looking behind the headline led me to learn about a family of transcription factors called PPAR. They seem to be promising targets for life extension drugs that are just beginning to be explored.
“In mice, GW501516, either when combined with exercise or at higher doses by itself, induces some hallmarks of [exercise] adaptation such as mitochondrial biogenesis, fatty acid oxidation, an oxidative fiber-type switch and improved insulin sensitivity via AMP-activated protein kinase (AMPK)” [source]
Sounds pretty good, doesn’t it? But
“To its detriment however, tumorigenic effects of GW501516 have been reported and development was discontinued by Glaxo in Phase II clinical trials.”
How serious is the risk of cancer? Are there ways to separate the benefits from the hazards, either by combing with other drugs or by chemical modifications to the structure of GW501516? Is there anyone with a lab who is seeking answers to these questions?
Personally, at age 68 the three main ways that I feel my age are (1) decreased flexibility in yoga postures, (2) decreased speed in running and swimming, and (3) I can’t remember what the third one is. I have charted my steady progression. Swimming and running times are 30-35% longer than when I was 40, and increasing year by year on an accelerating schedule. Exercise is my personal biomarker for age. For reasons of vanity and vitality as well, I eagerly seek pathways to improved performance. I also think that the activities of GW501516 and other PPAR agonists suggest potential for life extension, though there seem to be no lifespan studies either in rodents or humans.
Much of my source for what follows comes from a new paper summarizing exercise-mimetic drug state of the art, and references therein.
PPAR stands for Peroxisome Proliferator-Activated Receptor. Peroxisomes are organelles in every cell that specialize in breaking down fat into short chains that the mitochondria can burn. Thirty years ago, PPARs were discovered in the context of making more peroxisomes, but we now know that their most important function is to increase insulin sensitivity and signal a switch from burning sugar to burning fat.
Stimulating PPAR-α lowers LDL cholesterol and blood triglycerides.
PPAR-γ is a transcription factor that controls creation of new mitochondria. (Mitochondria are the source of cell energy, and as we age, we have fewer of them and they become less efficient, linked to all diseases of age. [from my blog last summer: Part 1, Part 2] Stimulating PPAR-γ improves insulin sensitivity and atherosclerosis. PGC-1α is a protein that turns on PPAR-γ, indirectly creating more mitochondria. Activating PPAR-γ has been discussed as an anti-cancer strategy.
Stimulating PPAR-δ (the modus of GW501516) switches the body from a preference for burning sugar to burning fat. Great for weight loss and also for endurance. You can double the running endurance of mice with GW501516. Presumably, it was rather effective in enhancing performance in human long-distance runners before it was banned in 2009. In calorie-restricted mice and long-lived mutants, PPAR-δ is overactive. (I’ve seen PPAR-β referred to only as similar to PPAR-δ. Maybe they’re the same.)
Joe Cohen at Self-Hacked sings the praises of GW501516. Comments on this blog claim that (1) the increased cancer risk in rats was at very high doses*, and (2) the mechanism in rats doesn’t apply to humans. Other commenters also minimize the cancer risk, but don’t offer references, and they may well be trolls for the companies that profit from GW501516.
“Although peroxisome proliferators have carcinogenic consequences in the liver of rodents, epidemiological studies suggest that similar effects are unlikely to occur in humans.” [source, ref, ref, ref, ref, ref]. “A number of experimental observations suggest that there is a species difference between rodents and humans in the response to PPAR agonists.” [same source] The article goes on to say that PPAR agonists may be more likely to create cancers in rat livers than human livers because rat livers have 10 times the PPAR expression compared to humans. It may be that tumorogenesis comes from the function for which PPARs were named: multiplying the number of peroxisomes. But we now know that PPARs promote new peroxisomes in rodents but not in humans.
Here’s what I’ve been able to find out about PPARs, GW501516 in particular, and cancer:
PPAR is upregulated in colon cancer cells. This shows that cancer causes PPAR, but not that PPAR causes cancer. There are many articles like this one, comprising evidence that activation of PPAR-δ promotes growth of existing tumors of the colon. The evidence is indirect, and gives no suggestion of the magnitude of the risk in humans who have colorectal cancer, let alone whether it in implies a risk for people who don’t have colorectal cancer.
PPAR-δ increases expression of COX2, the opposite of what aspirin and NSAIDs do. NSAIDs decrease risk of cancer, and this suggests both that PPAR-δ increases risk of cancer and that the effect may be offset with NSAIDs.
There are no studies in humans. There are many websites selling Cardarine, from which I guess that at least several thousands of people have taken taken it since 2005. I have seen no sales numbers or estimates of the number of self-experiments, let alone cancer statistics. I have been unable to locate any anecdotes about cancer.
This 2004 review preceded GW501516, and reaches no conclusion. It does, however, state baldly that PPAR-γ (not δ) is generally anti-cancer and that PPAR-α (not δ) causes cancer in rats but not in humans.
I have been unable to find published reports of the origina Smithkline-Glaxo experiment with rats that led to concern about cancer and abandonment of GW501516.
SR9009 is an unrelated mitochondria-growing drug sometimes mentioned in the same articles as GW501516. There are no studies suggesting that it is carcinogenic, but that may be because it is much newer and there are so few studies altogether.
I don’t know whether Cardarine is too dangerous for human use, or whether similar drugs can be developed that target PPR-delta more safely. But I’m outraged that the decision to abandon research on Cardarine has been made by investors in a board room who have no concern for public health and consider only the corporate bottom line. This is an example of the worst kind of collision between capitalism and medicine–a collision which claims millions of casualties each year in the US alone.
I can’t blame the suits in the board room for doing their job, marching to the tune of those who paid the piper. But this is emblematic of a gross failure of our regulation system, the FDA, and the reliance on for-profit drug companies to decide on our nation’s research priorities. We now have (presumably) thousands of people taking a drug which may have large benefits and may have large dangers. Most of them are motivated by wanting to be more buff or more sexy, and they are paying little heed to long-term consequences. And because FDA has washed its hands of responsibility, there is no one even keeping records or collecting data to learn from the massive experiment about long-term health effects of GW501516.
- Splicing Factors rescue senescent cells
I must admit that RNA splicing factors weren’t on my radar until this week, but I find this new experiment pretty convincing. Eva LaTorre and colleagues from University of Exeter (UK) claim that splicing factors, more than sirtuins, are the pathway by which resveratrol (and analogs) extend life.
Sections of DNA (genes) are transcribed into messenger RNA, which finds its way to ribosomes, where the mRNA is translated into protein molecules. But there is an in between step (in eukaryotes, but not in bacteria). The DNA contains not whole (contiguous) genes but pieces of genes that need to be spliced together to assemble instructions for a whole protein. Large sections of the DNA, called introns, are not intended for coding, and they need to be spliced out. And, in fact, the pieces can generally be spliced together in different ways to make different useful proteins. The work of splicing is performed by molecular complexes called splicing factors. This is a process to which I had not given much thought until reading this article, but apparently it is a crucial step in epigenetics. Epigenetics, the process of turning genes on and off, seems to get more complex with each passing year.
Resveratrol was identified about 15 years ago as a compound that extends lifespan in many species (but perhaps not in mammals). Resveratrol has many effects, but the primary mode of action has been thought to be through SIR2 (or SIRT1) or related compounds called sirtuins that are selective gene silencers. But the LaTorre group set out to show that the anti-aging benefit was through splicing factors rather than sirtuins. They synthesized variations on the resveratrol molecule and tested them until they found one that promotes slicing factors but has no effect on sirtuins.
Using this resveratrol analog, they were able to turn senescent cells back into fully functioning cells, with restored telomeres and other epigenetic changes. They demonstrated that this was accomplished through splicing factors, and without sirtuins.
All this was done in (human) cell cultures, and it the horizons are now open to see what effect such rejuvenation has at the whole body level.
* Of course, there is no established dosage for GW501516, but pills come in 10mg and 20mg typically, corresponding to ~0.1 to 0.3 mg/Kg. The highest doses I’ve seen discussed in humans are ~2mg/Kg daily, nominally the same as the rat dosage.