One Week, Two Innovations in Aging and Health

Incremental advances in understanding the genetics, epigenetics, and biochemistry of aging are gradually pushing the field forward.  In addition, there are occasional new ideas that have the potential for quantum advances that change the nature of the game.  Last week, there were two game-changers, originating from the US East and West coasts.

  1. Caloric Restriction has been the surest and best-documented way to add a few years to human life expectancy, with additional benefits for health and vitality along the way.  But few people have the discipline to stick with a restricted diet year after year, and in fact average BMI has been increasing for decades in America and Europe.  Valter Longo (U of S Calif) has been promoting the idea that intermittent fasting offers most of the benefits of CR, while demanding less discipline.  Last year, he documented impressive benefits from periodic fasting on water for 3 to 5 days.  Most people who try this practice compensate when the fast is over, and quickly gain back the weight that they lost; nevertheless the benefits persist.  This week, Longo offers us a 5 day diet that induces many of the same benefits as fasting, but need not disrupt anyone’s life, comfort, or energy level.
  2. The search for drugs that extend human life has been held back bureaucratically by the FDA’s  outdated idea of what a drug is for.  A drug can only be recognized or approved if it treats a disease, and aging is not a disease.  In fact, there are existing drugs that modestly slow aging (e.g., aspirin, melatonin) but they have been approved on a different basis, for different uses.  Nir Barzilai (Einstein College of Medicine) is a respected and well-established researcher who has thrown his reputation behind an initiative to change the FDA’s position.  He has designed a drug trial for metformin, the oldest and best treatment for Type 2 diabetes, to determine whether it can slow aging.  Of course, a great deal of pre-existing data suggests it will pass this test, and Barzilai will then propose that metformin be approved as a prescription for people not diagnosed with diabetes, as a preventive for cancer, diabetes, Alzheimer’s Disease, heart disease and stroke.

 

Allowing People to Eat While They’re Fasting

I got my start in aging science in 1996, after reading an article on Caloric Restriction by Richard Weindruch.  My first act as a researcher was to write a letter (USPS, not an email–this was 1996) to Weindruch and ask whether the timing or the kind of food mattered for life extension. “Not at all,” he answered, “calories are the bottom line.  Just make sure you get all necessary nutrients.”

Weindruch was well-informed, and what he said was state-of-the-art science in 1996, but today we know better.  Restricting protein and restricting particular nutrients have been shown to deliver some of the same benefits as a CR diet; and intermittent fasting has been validated as a life extension program in rodents, with strong evidence that it will work in people, too.  It’s a good thing, because sticking to a low-calorie diet is hard for most people.  Now Weindruch is approaching retirement and his compatriot Roy Walford left us in 2004.  Valter Longo  has picked up the mantle of practical CR research where they left off.

As I have come to expect, Longo does his homework.  The new publication is convincing because it combines theory and history with longevity studies in mice and yeast, and metabolic data from a new short-term trial in humans.

 

The Diet

The FMD (fasting-mimicking diet) is ketogenic, with restricted protein and a high percentage of calories from fat.  “Day 1 of the diet supplies 1,090 kcal (10% protein, 56% fat, 34% carbohydrate), days 2–5 are identical in formulation and provide 725 kcal (9% protein, 44% fat, 47% carbohydrate).”   The diet is predominantly fat.  The closest single food that approximates these macronutrient ratios is the avocado.  The diet approximates two avocados per day.  But you could construct the same macronutrient ratios using rice or apples and adding vegetable oil or small quantities of nuts.  I assume that green leafy vegetables could be added to the diet without changing its effect, while making it more palatable and filling and giving you a vehicle for the vegetable oil.

Here are three sample menus of my own construction (don’t blame Longo), each designed to give you ⅓ of the FMD nutrients for Day 1 or ½ the nutrients for Days 2-5.

Sample Meal One:
4 oz salad greens + 4 oz cucumber
1 tbsp vegetable oil
1 tbsp vinegar
½ apple (~4 oz)
½ oz almonds

Sample Meal Two:
6 oz cauliflower
1.5 oz sesame tahini
1 oz lemon juice
4 oz blueberries

Sample Meal Three (red cabbage salad):
4 oz shredded red cabbage
3 oz shredded carrots
½ oz cilanthro
½ (mushed) avocado (~3 oz)
1 tbsp lime juice
2 tbsp apple juice
¾ oz walnuts
garlic and mustard to taste

Sample Meal Four (gazpacho):
12 oz canned or fresh tomatoes
4 oz fresh onion
1 tsp olive oil
4 oz black olives
2 tbsp vinegar
4 oz cucumber
3 oz snap peas
salt, black pepper, cayenne
(Blend together, leaving it chunky or smooth to taste)

Spice to taste–the effect on calories and macronutrients is negligible.  Salt freely and supplement with magnesium.

 

The Data, mice

Mice were put on the FMD for 4 days, twice per month, starting when they were already middle-aged (16 months for mice ~ 50 years for humans).  They lived 11% longer than control mice (median) though maximum life span was not increased.   There was some indication that the mice were unable to tolerate the FMD intervals when they were really old, that it was triggering their death, and the experimental protocol was modified so that FMD intervals were stopped when the mice were 29 months old (the human equivalent of 90 years).

Test mice fully compensated for the lost calories when they were returned to ad libitum feeding, but still they weighed less–same lean mass but less visceral fat.  FMD mice had improved cognitive performance, stronger immune systems, lower markers of inflammation, and lower fasting blood sugar.  When they died, it was less likely to be of lymphoma, which is what usually kills lab mice.

 

The Data, humans

Humans were on the FMD diet 5 days out of each month, in a preliminary test that ran for three months.  Like the rodents, humans compensated for the lost calories when they returned to free eating, but still lost weight (not lean mass, but body fat).

Blood sugar and markers of inflammation were down; fasting insulin and IGF-1 were lower.  The article made no mention of HDL or LDL cholesterol.  Longer term trials with more criteria for metabolic health are planned.

In case you can’t tell, I’m really impressed with Longo’s work.  I think he has advanced the practice of human nutrition in the last few years more than anything that has been done in decades.

 

Legitimizing Research in Anti-Aging Medicine

We already have, incidentally, a great deal of information about the benefits of metformin in people with Type 2 diabetes (T2D, or metabolic syndrome).  It has been the first-line drug for T2D for fifty years, and about 150 million people are taking metformin worldwide.  The huge numbers have made it easy to collect data on other diseases.  People taking metformin have lower rates of cancer, heart disease and dementia than people taking other diabetic drugs.  It is tempting to conclude that metformin forestalls the diseases of old age generally, but rates of all these diseases are already elevated in people with T2D.  The new question being asked is whether metformin will offer benefits for people who don’t have diabetes to begin with.  There is one Scottish study reporting that cancer rates for diabetics taking metformin are depressed below the rate for non-diabetics who don’t take metformin.  Now that’s promising.

Nature reported last week that FDA had scheduled a hearing on Wednesday past (6/24) to consider a proposed drug trial for metformin as an anti-aging remedy.  The protocol would be to identify patients who have symptoms of one of three age-related disease:  cardiovascular disease, cancer and dementia.  People with T2D would be excluded by design.  Subjects would be prescribed metformin or a placebo, and the researchers would look for an effect on the other two diseases.  This design is a clever compromise between bureaucratic requirements and clean experimental methodology.  The bureaucratic requirement is that people assigned to take the drug must already be diagnosed with a recognized disease.  But it is the potential of metformin to reduce risk of the diseases that the subjects do not have that is the target question for the study.

Barzilai already has a small, ongoing trial for metformin and aging registered at ClinicalTrials.gov.  Just 15 patients will be enrolled, and the plan is to look at their gene expression profiles to see if metformin has an anti-aging effect.  A growing number of researchers (including me) thinks that gene expression drives aging, and last year, Steve Horvath of UCLA published a protocol for measuring physical age of the human body by combining epigenetic markers (methylation) from hundreds of different chromosome sites that empirically appear most sensitive to age.  They use the acronym MILES for Metformin In Longevity Study.

The new study is far more ambitious.

Plans call for the trial to enrol 3,000 people aged 70–80 years at roughly 15 centres around the United States. The trial will take 5–7 years and cost US$50 million, Barzilai estimates, although it does not yet have funding.

That’s $17,000 per patient, for a drug that costs pennies.  Certainly the cost will hold up this project, and monitoring patients for diseases that are already covered in their annual physicals.  Why does it need to be so expensive?

I have written to Barzilai about the Wednesday meeting with FDA and he would only say to watch for an article in next week’s Science magazine.

 

In the Larger Scheme…

The shortcut to modest gains in longevity is to work with the body’s adaptation to caloric restriction.  CR is known to work in many different animals, and is known to offer health benefits in humans, (although human longevity studies are probably completely impractical).  So the search is on for “CR mimetics”, drugs that will put the body into a calorie-deprived state without actually having to eat less.  Intermittent fasting, the Longo diet, and metformin all work on the same pathway as CR.  Some researchers believe resveratrol works on this same pathway, and even for rapamycin there is significant overlap with the CR mechanism.

It is understandable that researchers should be investing their time and pharmaceutical companies their money in this area, because this is where returns on investment are surest.  But the potential of this approach is limited to a few years of life extension, and layering metformin on CR on fasting on resveratrol on rapamycin will not add more years, just the same few years many times over.  As I have said in previous columns, there is immediate potential in telomerase activation, and longer term my highest priority would be to understand the epigenetic changes that come with age.

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Correlation and Causation–Nuts and Chocolate

Nuts are a big part of my diet.  It’s my habit to eat handfuls of nuts through the day, and a few times a week to incorporate almonds or cashews or peanuts into a main course.  Perhaps I should be cheering that a headline in ScienceDaily last week told us, “Nuts and peanuts (but not peanut butter) linked to lower mortality rates, study finds”.  So, is the study good news for me?  I can answer with assurance: “Probably.”  

The headline referred to this study, just published in the Journal of Epidemiology.  The researchers in Maastricht looked back at data from a Dutch survey on diet and mortality conducted from 1986-1997.  They found mortality rates of nut-eaters were 23% lower than people who reported eating no nuts.  23% lower mortality corresponds to 2½  years of life extension [how to calculate].  Threshold for the benefit was quite low at a few ounces per week, and more was not better.  (Past studies indicated that perhaps more is better.  I eat about 2 pounds of nuts in a week, perhaps over the top, because I like them and because I’m on a low-carb vegetarian diet.  There is no data in that range.)  Peanuts were found to be just as good as “tree nuts” (almonds, cashews, walnuts, Brazils, etc.) but peanut butter had no benefit whatever.

By itself, a finding like this is hard to translate into a dietary recommendation.  There are qualitative problems with methodology.  People are different, and a diet that is right for one person may be all wrong for another.  And if we eat more nuts, are we adding more calories?  Or are we eating less of something else?

There is also the quantitative problem of cross-correlations–correlation does not necessarily imply causation.  People who eat nuts are likely to be richer and better educated and more careful about their diets, likely to be eating less unhealthy snacks, less meat, less carbohydrates.  Any of these things could produce an incidental statistical association between nut consumption and longevity, with no indication that eating nuts confers a benefit.

Nut consumers were on average somewhat younger, leaner (in women), drank more alcohol, ate more vegetables and fruits, were less often hypertensive or never smokers (women), but were higher educated and more often used supplements, or postmenopausal hormone replacement therapy (HRT). Women with the highest nut consumption less often reported diabetes. [ref]

 

Cross-checking and corroboration

It’s common to correct with multivariate analysis, but multivariate analysis doesn’t work very well if there are more than a few variables, and it’s hard to know in advance which are the relevant ones.  Statistics ends up being an art as much as a science.

So the study gains credibility when previous studies, with different methodologies in different populations, come to the same conclusion.  There are several, the biggest and best of which are this one and this one.  With write-up of the new study, the authors include a “meta-analysis” of these past studies.  This is another layer of statistics which combines previous results to come up with a conclusion stronger than any one study could draw.  Meta-analysis is a pursuit that can keep a data geek happy and productive for weeks on end.  Happiness and productivity are both positively correlated with life expectancy ☺.

Though a self-identified stat geek, I confess to being unfamiliar with Cochran, Begg and Orsini; nevertheless a paragraph like this adds to the credibility of a study in my eyes:

In these analyses, the HR estimate for each study was weighted by the inverse of the variance of the log HR to calculate the summary HR and its 95% confidence interval (CI). Heterogeneity between studies was estimated using the Cochran’s Q test and I2 (the proportion of variation in HRs attributable to heterogeneity).  Publication bias was assessed by the Begg test.  In addition, we performed dose-response meta-analyses using generalized least squares regression described by Orsini et al. with restricted cubic splines (four knots, at 5th, 35th, 65th and 95th percentiles) to investigate potential nonlinearity in the dose-response relationship.

The multi-study meta-analysis results closely paralleled the present study.  All the diseases of old age were lower in people who ate nuts; cancer was marginally lower, and cardiovascular disease much lower.  Some of the older studies found less benefit for peanuts than for tree nuts, and beyond a few ounces a week, there was ambiguity about whether more nuts offered more benefit.

 

Chocolate

There is comparable statistical evidence for the benefit of eating chocolate!  For years, I have refused to take these studies seriously, figuring that they are funded by a consumer industry that is eager to rehabilitate its junk-food image.

And in fact, just last month there was a spoof done by a science journalist, intending to remind us how easy it is to lie with statistics.  The headline was “Slim by Chocolate”.  Here is  John Bohannon’s account of what he did, and what morals we should draw.  His main point is that we all should use our common sense and be skeptical of sensational health claims.  Who can argue with that?

But the topic he chose incidentally illustrated other points as well.  There are legitimate claims for health benefits from chocolate.  People are complicated, and no two bodies are alike.  Not only do foods affect our metabolisms differently, but even more various are the psychological effects of foods.  There are people who find a little bit of chocolate uniquely satisfying, and it helps them to eat a leaner, healthier diet in many other ways.  There are other people who find chocolate addictive, and the more chocolate they eat, the more they want.

I find it completely plausible that some people are better able to lose weight with chocolate than without.

 

The psychology of eating is the most individual thing about diets, and it plays an essential role.

Time after time, human psychological studies have demonstrated that for the great majority of people, will power is worse than useless in trying to control weight.  (Present company, of course, is excluded.  You and I both have perfect control over what we eat, regardless of what the statistics may say.)  People who set out to lose weight by adhering to a set of rules generally succeed for awhile, then well over 90% bounce back to a weight higher than they started.  Habits in themselves are hard enough to change; but in addition we have powerful and persistent homeostatic impulses whispering in our ears.  The body gravitates to a “set point” in weight and percentage of fat.  The most successful diets all manipulate those signals of craving and satiety with alterations to the body’s biochemistry.

We joke about pregnant women having aversions to some foods and cravings for others.

Methionine is an essential amino acid, and it is normally part of all protein that we eat (though some sources have more than others.)  There have been a lot of studies of methionine restriction, in which mice are fed an artificial diet of re-constituted proteins in which this one amino acid is missing.  Despite the fact that methionine has no distinctive flavor or smell, mice know at some level that they are missing methionine.  Some researchers report that the mice refuse to eat unless there is methionine in their food.

The moral of the story is that our bodies know what they want, and will nag at us until they get it.

For some people, phytochemicals in chocolate can play a positive role in regulating gut biota and controlling anxiety that can lead to nervous eating and other destructive behaviors. This new study comes from University of Aberdeen in Scotland, and was published last week in the British Medical Journal.  All-cause mortality was not compiled, but the study claims that eating more chocolate is associated with less cardiovascular disease, and the group with highest chocolate consumption enjoyed 23% less heart disease.  Here is a meta-analysis of studies in the past that have been less clear and consistent than for nuts.  The average is that people who ate the most chocolate had 25% fewer cardiovascular events compared to people who ate the least.  No studies have been done about cancer, or all-cause mortality.

Interestingly, the non–chocolate-eating group had the highest mean body-mass index, the highest percentage of participants with diabetes, and the highest levels of inactivity. On the other hand, “higher chocolate intake was associated with a higher energy intake, with lower contributions from protein and alcohol sources and higher contributions from fat and carbohydrates.” [ref]

Translation: chocolate eaters weigh less despite eating more.  Did Mr Bohannon stumble onto something that none of us expected?  Probably not.  Here are two studies [one, two] that find just what we would expect, that eating chocolate is associated with weight gain.

 

The bottom line

People who eat nuts and chocolate have lower rates of cardiovascular disease and live longer than people with comparable amounts of body fat who don’t.  If you can adjust your diet to add chocolate and nuts without gaining weight, you will probably benefit.  Remember always that diets are individual and the response of your own body is not the average response.

This is the era of big data.  We are awash in data.  What fun for people like me, who love to extract meaning from numbers!  Still, answers to basic questions remain elusive.  Finding correlations between single foods and particular diseases is a start.  But researchers might remember that our goal is to design diets and life styles that are healthy and adapted for each individual.  We have a long way to go.  More creative and ambitious study designs for the future might help.  I’ll have two examples for you next week.

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Dreams of a Pill to Enable Regeneration

Eight years ago, I assumed erroneously that the chute of my food processor was longer than my fingers.  I lost a quarter inch from the tip of my right middle finger.  Today, my finger has grown back, right down to the pattern of the fingerprint.  I am fortunate to be a good healer.  This is the extent of regeneration that adult humans can normally expect.

Many “lower” animals can regenerate large parts of their bodies when damaged.  This includes not just the legendary cases of starfish and planaria worms, but also zebrafish and salamanders.  Porpoises that have suffered deep and severe lacerations in encounters with sharks regenerate their skin quickly, without scarring.  So why can’t we?

It has long been assumed that mammals have “lost” the capacity for large-scale regeneration, and the cellular machinery is no longer present.  But 20 years ago, Ellen Heber-Katz (then at Wistar Institute in Philadelphia) noticed that a strain of mice in her lab routinely erased the ear punches that her lab used to identify them.  There was no scar or mark where the hole had been punched a few weeks earlier.  She was curious enough to investigate what was different about these mice, and traced the ability to a defective gene–a defect in a gene that shuts off regeneration.  She turned on a dime, put aside her research on immunity, and set about to breed this mouse, to study the biochemistry of this defect, and the latent power of the mouse to heal itself cleanly.  The defective gene was p21.  (read more from my blog from last year)

p21

p21

p21 plays a role in apoptosis, the elimination of cells that self-detect that they are damaged or dangerous or cancerous.  We might suspect that eliminating p21 would increase cancer, but that seems not to be true.  Apparently, p21 has both pro- and anti-cancer effects, and in fact, inhibitors of p21 have been studied as a strategy for treating cancer.  Mice lacking p21 can heal more effectively, and there seems to be no downside.

 

Prostaglandin inhibition

A headline in Science Daily this week announces identification of a drug that can dramatically increase healing capacity by blocking the enzyme that degrades prostaglandins.  Prostaglandins are eicosanoids, fats and oils that serve as signal molecules.  (Usually we think of signal molecules as proteins, or less commonly RNAs.)  Hormones circulate through the bloodstream and reach the whole body, but eicosanoids circulate locally, which is the definition paracrine signals.

If the word “prostaglandin” is familiar to you, it may have an association with headaches.  E2 is the most famous prostaglandin (PGE2), and PGE2 is associated with pain and fever.  NSAIDs including aspirin inhibit the COX enzymes (cyclo-oxygenase) which have a primary role in creation of prostaglandins.  This is not a side-effect but an important mode of action of aspirin.  Prostaglandins are pro-inflammatory.

We think of inflammation as destruction of tissue, and regeneration as renewing or re-building tissue.  So it seems surprising that prostaglandins should be involved so deeply in both processes.  But PGE2 is known to be associated both with inflammation and with anabolism, stem cell activity, and tissue formation.

Prostaglandins are constantly being created and degraded, signaling on a short time frame.  The amount of prostaglandin in the system is determined by a balance between production and destruction.  The new drug has already been promoted with the catchy name SW033291, and it is an inhibitor of 15-PGDH, which is the enzyme that degrades prostaglandin.

A team of scientists at Case Western (Cleveland) and U of Texas (Dallas) were searching for ways to enhance PGE2, based on preliminary evidence that it could promote healing.

Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. To date, therapeutic interventions have largely focused on targeting two PGE2 biosynthetic enzymes, cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), with the aim of reducing PGE2 production. In this study, we take the converse approach: We examine the role of a prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), as a negative regulator of tissue repair, and we explore whether inhibition of this enzyme can potentiate tissue regeneration in mouse models. [ref]

They noted that mice lacking the gene for 15-PGDH had twice as much PGE2, and these mice recovered more rapidly after exposure to radiation, or surgical removal of part of the liver.  They also had stronger immune systems, with more white blood cells.

 

Preliminary Findings from Heber-Katz Lab

Also new last week was a paper from the Heber-Katz lab, recently moved to the Lankenau Medical Center.  They have identified the protein HIF-1α as a target for therapy, and have preliminary, positive results for an injectible drug that enhances healing power to the level of the p21-null mice by promoting HIF-1α. “Increased expression of the HIF-1α protein may provide a starting point for future studies on regeneration in mammals.”  The chemical name of the drug is in the article, but it is not enlightening.

In a press release, Heber-Katz reports indications that the drug she is applying de-differentiates some “end-user” cells and restores their ability to act as stem cells.

“Our experiment shows the possibility of taking mature cells and, with addition of HIF-1a, causing dedifferentiation to a highly immature state where the cells can proliferate, followed by redifferentiation upon withdrawal of HIF-1a,” says Heber-Katz. “Many researchers in the field see tissue regeneration as a very complex set of events, but some of us look at it more as a process that needs to be turned on and allowed to go to completion. This is what is so exciting about what we saw with drug-induced stabilization of HIF-1a.”

 

So, What’s the Prognosis, Doc?

NSAIDs including aspirin have well-estalished benefits that lead to substantially lower mortality from heart disease, stroke and cancer.  NSAIDs work in two ways:  (1) reducing blood clotting, which is the proximate cause of most heart attacks and strokes, and (2) reducing inflammation, which is a deep cause of cancer, damage to arteries, and other ailments associated with age.  All these benefits are associated with reduced PGE2.

The new drug increases PGE2, and demonstrates some promising benefits that also have potential benefits against aging.  My guess is that this is a hint of something important, but that SW033291 itself is unlikely to have a net benefit for longevity, because its action is opposite to aspirin.  (Garret FitzGerald expresses this caution in a Perspective piece accompanying this week’s Science article.)

The benefit will come when next-stage science learns to tease apart the benefits of enhanced regeneration from the liability of increased systemic inflammation.  There is every reason to believe this is possible, but the intervention will have to come at the next level down from PGE2.

As for the HIF-1α stabilizers, the challenge at this point is that this approach requires repeated injections of time-release capsules of the drug, which has a short lifetime in the body.

Where are the p21 inhibitors?  I can find no literature on p21 drugs being studied for regeneration.

 

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Is there an Aging Clock in the Hypothalamus?

The brain does its work with electrical signals through a network of neurons.  The information is passed to every cell in the body with chemical signals, hormones, RNAs and proteins that are dissolved in the blood.  The interface between the electrical and the chemical networks is a tiny region in the middle of the brain, the hypothalamus.  

I believe that aging is centrally controlled on a schedule.  Most researchers don’t believe that yet, but everyone accepts broad evidence that the timing of aging can be modified by central signals.  All the signals about hunger and stress and sex, etc, that affect aging must somehow be integrated into a decision.  It seems logical that this happens in the brain, and messages are passed to the body through chemical signals.  This is a process that is just beginning to be understood, but the biochemists who study regulation to the brain are looking to the hypothalamus as a probable center for time-keeping, decision-making, and broadcast of chemical signals that regulate aging.  We may hope that if the hypothalamus thinks we are young, then it will make us young.  (I discussed some background in this space 2 years ago.)

The idea is emerging in recent years that aging is controlled by the same epigenetic clock as development, continued through the life time after growth has come to an end.  [Rando, Blagosklonny, Mitteldorf, Magalhaes, Johnson]

Growth and sexual maturity are controlled by secretions of the hypothalamus and the pituitary, which is just below the hypothalamus [background].  Sex hormones themselves come from the genitals, but they respond to signals from the hypothalamus, in the form of GnRH, gonadotropin-releasing hormone.  (Timing for sleep/wake cycles is controlled through melatonin from the pineal body, which is part of the epithalamus, just behind the hypothalamus.)  [basics]

source:  http://antranik.org/the-diencephalon

source: http://antranik.org/the-diencephalon

 

Orexin aka Hypocretin

Orexin (also called hypocretin) is a neurotransmitter protein, just 33 BP long, associated with wakefulness, alertness, appetite and cravings.  Mice lacking the gene for orexin display narcolepsy.  They are continually falling asleep, only to waken a few moments later.

Orexin is produced in a tiny region of the hypothalamus.

Drugs that block orexin have been developed recently as aids in overcoming addiction.  There are also applications for insomnia.  Orexin makes you awake and alert; blocking orexin helps facilitate sleep.

The “rate of living” hypothesis is an old, discredited theory–such ideas take a long time to die.  You might expect that orexin speeds you up, so it shortens life span.  The opposite is true.  Orexin speeds you up, and it increases life span.

Mice that are genetically modified to have no orexin tend to obesity–again this is counterintuitive, if you think of orexin as an appetite hormone.  Mice that have no leptin (ob/ob) are found to have lowered levels of orexin.  They are obese and have shorter life spans. This and other evidence suggests that orexin is beneficial for maintaining insulin sensitivity, avoiding diabetes.

Loss of insulin sensitivity is a core mechanism of human aging.  We have less orexin as we age.  Orexin helps maintain insulin sensitivity.  Putting these pieces together, we have a plausible rationale for looking for anti-aging benefits from increased orexin expression.

Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. [2009]

Orexin is not a large protein molecule, but large enough that it won’t survive digestion.  You can’t eat it because digestion efficiently destroys proteins, but there is a nasal spray with orexin that is being explored in experiments with animals and humans.

Mice with extra SIRT1 in the brain live longer, and the action of SIRT1 has been traced to the hypothalamus, and specifically to a stronger role for orexin. [ref]

NFκB is a hormone that promotes inflammation and is widely regarded as pro-aging.  In experiments with mice, NFκB inhibition extended life span by blocking GnRH in the hypothalamus [ref].

 

Neuropeptide Y

Note: I regret that this blog post is turning into alphabet soup.  Biochemistry is not my native tongue, and I tend to think that mapping the network of cross-relationships among hundreds or thousands of native hormones is not likely to lead to the silver bullet that we’re hoping for.  I’m still hoping that aging turns out to have a basis that is manageably simple, with a few chemicals at the control center.  But perhaps we have to map a good deal of the biochemical web before we can identify the controlling nodes.

Neuropeptide Y is another small neurotransmitter protein, in the news this spring because of work from the laboratory of Claudia Cavadas in Coimbra, Portugal.  Autophagy is the recycling and renewal of large molecules in a cell that become degraded over time if they are not refreshed.  Autophagy is dialed down as we age, leading to aging cells and an aging body.  The Cavadas group has identified Neuropeptide Y (NPY) as a signal that comes from the hypothalamus, and tells cells to keep autophagy up.  We have less NPY as we age, and people with Alzheimer’s and Parkinson’s diseases have less NPY.  The Cavadas team notes that NPY in the hypothalamus is increased in rats that are living longer due to calorie restriction.  The new experiments added NPY to cell cultures, and found that NPY promotes autophagy in vitro.  They went on to the more difficult experiment in live mice, using gene therapy to increase NPY in neurons only.  This caused the mice to eat more, so they were put on a feeding regimen where they ate no more than control mice that didn’t have extra NPY.  The treatment successfully upgraded autophagy, but left open the question of how much of this was due to caloric restriction and how much to the NPY itself.

Autophagy impairment is a major hallmark of aging, and any intervention that enhances autophagy is of potential interest to delay aging. However, itwas described that the hypothalamus is a brain area with a key role on whole-body aging. In the present study, we show that an endogenous molecule produced by the hypothalamus, the neuropeptide Y (NPY), stimulates autophagy in rodent hypothalamus. Because both hypothalamic autophagy and NPY levels decrease with age, a better understanding of hypothalamic neuronal autophagy regulation by NPY may provide new putative therapeutic strategies to ameliorate agerelated deteriorations and delay aging. [Source]

Previous experiments with rats had shown that whole-body overexpression of NPY leads both to 10% longer life span and better blood pressure control, without weight gain.  NPY is also associated with renewal of the immune system.

The Bottom Line

This line of thinking is still largely theoretical.  The only practical recommendation is to take melatonin at bedtime after age 50.  But it may be that the hypothalamus is ground zero for signals that tell the body how old it is.  (Here is a recent editorial from Buck Institute on the subject of neuropeptides and aging.)  I believe that the hypothalamus and its secretions are a promising area for new research, and that, over the next few years, basic findings will lead to the most powerful interventions to change the course of aging.

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Preserving Insulin Sensitivity

The body adjusts its rate of aging in response to environmental cues.  Most influential is diet.  The story I have told is that

  • The body decies whether food is plentiful (for pregnancy and childrearing) by sensing nutrition and body fat.
  • The body decides either “reproduce and die” or “hang in there and live longer”.
  • The medium for transferring the information is the metabolism of insulin, the pancreatic hormone that controls blood sugar.
  • Insulin resistance (type 2 diabetes) is a primary mode of aging.
  • Sugar and starches quickly become sugar in the blood.  Fat and fiber slow the absorption of sugar.
  • Fasting, exercise and foods with a low glycemic index contribute to better insulin sensitivity and longer life.

Glycemic index (GI) is supposed to be a measure of how rapidly a food is turned into sugar in the blood.  But as I have been reading about GI this week, the story gets muddier and muddier.  Glycemic index as reported is not a good measure of the body’s insulin response.  In fact, insulin response in some studies was found to have no relationship whatever to GI!  Combinations of food turn out to be very important.  Fiber and fats can be helpful, and there is a new category I have learned about recently called “resistant starch” which slows the absorption of other foods that are digested along with it.  Can drinking water with food slow digestion?  (I last blogged about this subject 2 years ago.)


The idea of “negative calorie” foods is very appealing.  Are there things that you can eat that actually make you thinner?  Are there foods that decrease the insulin impact of a meal, or that lead to lower absorption of food that is eaten together at the same meal?

 

Glycemic Index and Glycemic Load

Glycemic Index was conceived as a characteristic of food ingredients, something that could be reported on a label.  The way it is supposed to work is that low GI foods are better, especially for diabetics, but preserving insulin sensitivity is a concern for all of us as we age.  Glycemic Load (GL) was supposed to be equal to the glycemic index times the portion size.  But instead, the insulin response to food has turned out to be just as complicated as it can be

  • different people respond differently to the same food
  • the same person responds differently at different times
  • eating twice as much of a sugar or starch does not double the glycemic load (as was presumed in the early studies)
  • combinations of food cause a different response from the foods separately

Insulin is a signal to the body that “we have all the sugar we need, thank you.  Take your calories and turn them to fat.”  Insulin causes fat storage.  Insulin is associated with weight gain.  Weight gain and insulin resistance, together and independently, contribute to mortality risk.

 

Inscrutability of Tables of Glycemic Index and Load

I knew that Glycemic Index (GI) was designed to measure the surge in blood sugar that comes from eating a particular food.  It was my naive expectation that sugar would have the highest GI, then starches, then whole grains, then beans, then nuts.  I thought that greens and fish and meat would have very low GI.  But the GI reference table confounded my expectations on every score.

The glycemic load [GL] is calculated by multiplying the number of grams of carbohydrates in a given food by its glycemic index [GI] (which measures how quickly the food is converted into glucose and released into the bloodstream). The glycemic load is an accurate measure of how much insulin your body will have to produce to neutralize the carbohydrates in a given food. [LEF magazine]

Turns out that this very common-sensical statement is far from true.  The first thing I had to learn is that GI is not standardized by energy value of the food, but by grams of carbohydrate.  Say a peanut is being compared to a potato.  The potato is almost all carb, but the peanut is only ⅕ carb.  So when they compare the glycemic response head-on-head, they compare 50 grams of potato with 250 grams of peanuts.  Of course, this is going to make the peanut’s GI look bad.  The GL is supposed to correct for this, multiplying by a “standard portion”, but the whole idea of a “standard portion” is dubious.

By this same definition, meats and salad oils have an undefined GI.  This is not because they produce no glycemic response, but because they contain no carbs, so the GI measurement protocol is undefined.

Here is a table from Harvard Medical school, the top one that came up in a Google search.  In my experience, it is no more or less unfathomable than others.  For example:

  • Banana cake without sugar has a higher GI than banana cake with sugar.  But it has a lower GL.
  • Cannd chick peas have a GI of 38, while dry cooked chick peas have a GI of 10
  • Unsweetened Apple Juice has a GL twice as high as Coca Cola (30 vs 16) even though Apple Juice has a lower GI (44 vs 63)
  • Whole milk has a higher GI than skim milk (41 vs 32)

Perhaps you can explain the higher GI of whole milk if you assume that cream is finding a pathway to be burned as fuel within two hours.  And the low score for Coca Cola might have to do with burning sugar in response to cafeine.  But there are too many questionable numbers in this table for me to have any faith in it.

How is GI measured?

The GI value of a food is determined by feeding 10 or more healthy people a portion of the food containing 50 grams of digestible (available) carbohydrate and then measuring the effect on their blood glucose levels over the next two hours. For each person, the incremental area under their two-hour blood glucose response (glucose iAUC) for this food is then measured. On another occasion, the same 10 people consume an equal-carbohydrate portion of glucose sugar (the reference food) and their two-hour blood glucose response is also measured. A GI value for the test food is then calculated for each person by dividing their glucose iAUC for the test food by their glucose iAUC for the reference food. The final GI value for the test food is the average GI value for the 10 people.  (Jennie Brand-Miller at Sydney University)

The big problem is in the “portion of food containing 50 grams of digestible carbohydrate”, which can be a very large or a very small portion, depending on the food.  Two additional problems are that different people have very different responses, and also that the body’s response to foods tested in isolation is not a good indication of how the body responds to food combinations typical of a meal.  In this study, GI for different breakfasts was computed by adding up the GIs for individual foods; when the subjects’ insulin response was measured it had no relationship at all to the computed GI—a correlation of zero.

 

Combining fiber with carbohydrates

Adding fiber to a meal can reduce the subsequent blood glucose and the insulin spike [ref].  Wheat bran has been used to slow the blood sugar uptake for diabetics [ref].  Green leafy vegetables have a similar benefit [ref, ref].

Resistant starch is, by definition, starch that resists stomach enzymes, and is not quickly digested.  It passes through the large intestine, where it is fermented by bacteria that thrive on it.  RS may cause flattulence or indigestion.  Often the symptoms clear up after a few weeks.  Green bananas and raw potatoes are natural sources of RS.  You can also buy it as a flour and mix it into foods.  This study claims that resistant starch slows starch absorption and damps the insulin spike better than fiber.  In this study, RS lowered fasting glucose and improved blood lipid profiles. Glucomannan (konjac), pectin, and guar flour are all reported to have similar effects to RS.

Personally, I have a hunch that fiber (and possibly resistant starch) change the intestinal flora in a way that lowers total food absorption.  You extract fewer calories from the same food.  However, this is almost impossible to measure directly, and to my knowledge the study has not been done.  Less controversially, adding fiber or RS to the diet affect your appetite and how full you feel, and affect the insulin response, which influences whether your body burns the calories or adds to fat stores.  In all events, I think it’s worth the experiment to see if you can lose weight by adding fiber to your meals.

In this context, it is no surprise that long-term studies show that diets rich in green leafy vegetables [ref, ref, ref] and high in fiber [ref,ref, ref, ref] lower the risk of chronic disease.

 

Water

Drinking water with food, or eating foods with high water content, dilutes the food in your stomach.  I find it reasonable that this alone should slow digestion, delay the absorption of sugar, lowering the effective glycemic load.  Is this a substantial benefit, or is it negligible?  I have been unable to find any data on this question.  There is good evidence that peope tend to eat less calories if they drink more water, especially right before a meal [ref], so water can be a psychological aid to weight loss.  Eating foods with high water content also increases satiety, so that (most people) tend to eat smaller meals, and don’t make up the difference later [ref].  Soups are a weight-loss strategy.

 

Supplements and drugs that can damp your insulin response:

  • Chromium and magnesium.  These are minerals with no down side.  Recommended for all.
  • Metformin.  This is a classic diabetes drug, so powerful that diabetics taking metformin actually have a lower mortality rate than non-diabetics who don’t take metformin according to a Scottish study last year.
  • Cinnamon and vinegar, green coffee extract and irvingia are among many substances that can be taken 20 minutes before a meal to suppress the insulin spike.

 

Is Fructose worse than Sugar?

All sugars contribute to insulin resistance and accelerate aging.  Are some sugars worse than others?

Table sugar is sucrose, a 12-Carbon sugar.  It is made of two 6-Carbon sugars, a “dimer” of fructose and glucose.  High-fructose corn syrup (HFCS) has more fructose than glucose (55-65%) and honey is similar.  Agave is yet higher in fructose.

The name “fructose” would suggest that it is the sugar of fruits, but fruits in general don’t tend to have more fructose than glucose.  Apple sugar is about 75% fructose, and melons are 65-70% fructose, but grapes, peaches, and berries are 50%, and bananas actually have less fructose than glucose. [from FoodIntolerance.org]

Whether fructose or HFCS is worse than sugar has become a controversial question.  Life Extension magazine and Mercola.com are down on fructose, while Examine.com and other health advice sources tend to minimize the difference.

Both glucose and fructose go directly into the bloodstream, but glucose is the body’s primary fuel, so the insulin response is determined by the glucose.  In terms of insulin spike, fructose is a lot better than glucose.  Fructose has a much lower GI than glucose.

(from a new study in PNAS http://www.pnas.org/content/112/20/6509 )

(from a new study in PNAS http://www.pnas.org/content/112/20/6509 )

Despite this, there are two lines of argument against fructose

  • The sweet taste without the insulin was found in this new study to interfere with natural appetite control, increasing desire for more food.  But the difference was not dramatic, as measured either by subjective reports or fMRI.  Satiety and hunger are said to be ruled by leptin and ghrelin, respectively.  Leptin and ghrelin responses to glucose and fructose were not different in this study.
  • In the liver, fructose is converted not to glucose, but to triglycerides, which are stored by the body as fat.  There is broad evidence both from animals and humans that fructose is more fattening than glucose [ref, ref].  This is the basis for the argument that, in the long run, fructose leads to weight gain, insulin resistance, more type 2 diabetes, and thus more accelerated aging than glucose.

The best reference I’ve been able to find on the subject is Basciano et al, 2005.

Everyone agrees that it’s best to minimize both glucose and fructose.  If you prefer to sweeten with glucose instead of fructose, it’s sold as dextrose, not as cheap as cane sugar, but cheaper than honey or agave or maple syrup.

 

A Calorie is a Calorie is a Calorie – Not!

“The amount you weigh is exactly the difference between the calories you ingest and the calories that you burn exercising.”  We hear this all too often.  Writers who should know better promote it as the “First Law of Thermodynamics.”  This is dangerous nonsense.

In fact, the calorie content of a food is measured simply by burning it and collecting the heat that is released.  But the body’s efficiency in use of foods is a very complex affair, dependent on everything from how well you chew your food to which bacteria reside in your intestine.  Peanuts do not deliver the body as many calories as peanut butter. There are (lucky?) people with very inefficient metabolisms and (unlucky?) people whose bodies are able to extract every last calorie from any meal.  The bacteria that live in our guts digest food for us, but extract a toll in energy that they need for themselves.  Depending on the particular bacteria you have in your intestine, the toll may be only 10% of the food energy coming in, or close to half.

Roughage slows calorie absorption and helps to move food quickly through the intestine, with less total absorption.  Eat as much raw wheat bran as you can stomach, and think of it as a negative-calorie food.  A vegetarian raw foods diet is not for everyone, but if you can live with it, it is a sure way to lose weight.  Raw foods are poorly absorbed, and from our perspective, that’s a good thing.

 

The Bottom Line

Weight gain or lost is probably a good proxy for how well you are controlling your glycemic load.

Remember that weight is relative to your genetic body type.  A person who has a genetic disposition to being overweight is not at higher risk for diseases of old age unless he actually eats too much.  Conversely, people who are blessed with a “thin metabolism” can be unhealthy if they overeat, even if they don’t look fat.  If you tend to being overweight and have to diet and work out constantly to keep your weight just above “normal”, you are in the optimal position for health and longevity. [Read more]

I suggest that you use your instincts and your experience to lower your glycemic response to food, and not to waste time with the mysteries in the tables of glycemic index.  First cut out sugar, then work on reducing starch.  Refined carbohydrates are worse than whole grains, but in my own diet I’ve eliminated all bread, pasta, rice, grains, and potatoes—so I can attest it’s possible.  Beans and nuts are good protein sources if, like me, you don’t eat meat.  My vegetarian version of the no-starch diet leads to moderate ketosis, less extreme than in a meat-based diet.

Combine fiber into every meal.  Eat large salads and other green vegetables.  Add raw wheat bran and/or resistant starch to your foods.

Everyone should be supplementing with magnesium.  Consider chromium and metformin as well.

Eat soups.  Drink water before and during meals.

Fasting is a powerful way to preserve insulin sensitivity.  Concentrating all your daily eating in an 8-hour window counts as a short, daily fast [read more].  Longer fasts of one to four days have major benefits [read more].

Exercise is the best general tonic for general health.  Exercise before meals in particular is a great habit to culture.  Even a minute or two of vigorous exercise that gets you panting makes a big difference in your glycemic response to a meal.

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Vital Questions, Part 3

Week 3 – continued review of The Vital Question by Nick Lane

Nick Lane takes a look at the evolution of life on earth with an eye to explaining large-scale patterns, from a perspective based on the energy metabolism.  In the first week, we talked about the origin of life and the structue of the cell.  In the second week, we looked at the differences between eukaryotes and what came before, and asked about mergers of widely differing species.  In this third and final installment, I want to look at sex and death, and also to advocate for two important concepts that could broaden Lane’s perspective yet further.

 

 

Sex

Sex is the exchange of genetic material.  It was invented long before the first eukaryote.  Bacteria freely pass circular snippets of DNA called plasmids among themselves, with little regard to where they came from or what they are for.  But in eukaryotes, sex became formalized, with exchange strictly limited to another of the same species (this is the definition of species), and it became compulsory, a prerequisite for reproduction in multi-celled species.  Many plants and some animals are hermaphrodites, with both male and female in one individual.  But most higher organisms have two separate sexes.  Lane proposes to explain all these patterns based on the most fundamental observation:  the mitochondria, having colonized the eukaryotic cell and brought with them their own DNA, have to remain healthy and work hormoniously with the host cell.

bacteria enjoy the benefits of sex (fluid chromosomes) along with the speed and simplicity of cloning. But they don’t fuse whole cells together, and they don’t have two sexes, and so they avoid many of the disadvantages of sex. They would seem to have the best of both worlds. So why did sex arise from lateral gene transfer in the earliest eukaryotes?

This is an (uncharacteristic, for Lane) understatement.  For anyone who thinks in terms of the dominant paradigm of the 20th Century, evolution is all about individual competition and selfish genes.  Plasmids, as selfish genes, make perfect sense.  But the way that sex is implemented in eukaryotes makes no sense from the perspective of selfish gene theory.  The most successful members of the community have combinations of genes that work better than anyone else’s.  What incentive do they have to share genes with their competitors, bringing their fitness down and their competitors’ fitness up?  And the biggest violation of selfish-gene logic is the “cost of males”.   Hermaphrodites have twice the fitness compared to diecious sex (2 separate sexes).

The standard view is that this is a mystery, an isolated phenomenon that has yet to be reconciled with selfish gene theory.  I prefer to think that diecious sex is an unequivocal refutation of selfish gene theory, that evolutionary theory must expand to embrace a notion of fitness more sophisticated than “every gene for itself”.

 

Origin of Sex

Eukaryotes were around for half a billion years as single-celled protists.  Like bacteria and archaea before them, they were single cells, but the cells were 100,000 times larger and had a great deal of structure and mechanics that the prokaryotes didn’t have.

Lane says sex arose very early in the history of eukaryotes.  He cites as evidence (1) that the long list of traits that all eukaryotes have in common (but that prokaryotes lack) could only have arisen in an inbreeding population; and (2) even the simplest eukaryotes today (giardia is the example that Lane cites) have the genes necessary for meiosis=cell mergers and gene exchange.

Cloning may produce identical copies, but ironically this ultimately drives divergence between populations as mutations accumulate. In contrast, sex pools traits in a population, forever mixing and matching, opposing divergence. The fact that eukaryotes share the same traits suggests that they arose in an interbreeding sexual population. This in turn implies that their population was small enough to interbreed.

In a diverse population sharing genes, it is possible for different lineages to evolve different features, and then these features come together in a single offspring when they mated.

An alternative hypothesis due to Margulis is that these diverse features were too different to have been encompassed in a single species (a single, interbreeding population).  Rather, the the different features that came together in eukaryotes evolved separately and then the separate species combined in rare cell-merger events, a process she wrote about as “endosymbiosis”, or acquiring genomes.

(How different are these two pictures, really?  We know that individuals with very different features must have shared genes; perhaps it is only a subtlety to ask whether these very different individuals were part of one wide-ranging inter-breding population, or of separate demes that might be called different species.)

 

Sex and Reproduction were Different Functions

In the one-celled eukaryotes, sex and reproduction were separate and unrelated functions.  Reproduction occurred by mitosis, simple cell division, producing two clones.  Sex occurs via conjugation, in which two individuals merge their cells, and merge the cell nuclei temporarily.  Their chromosomes mix, and as each chromosome finds its opposite number, genes can cross over between the two chromosomes.  When the merged cell comes apart, the two individuals that go their separate ways are no longer the same two individuals that came together an hour earlier.  Instead, there are two new individuals, each a hybrid.

 

Could mitochondria have “agitated for sex”?

Lane sees the cellular invasion by mitochondria as the source of everything eukaryotic.  Sex, as we have seen, is a particularly thorny problem—not just the mechanics, but the fact that (short-term) selective pressures should have been acting against it.  But while sex would not be adaptive for the host cells (in the short run), it would have provided the only effective way for the mitochondrial “infection” to spread.  There must have been a long transition period in which the mitochondria were not fully domesticated, and had their own ideas about what it means to be “adaptive”.  After mitochondria learned to be endosymbionts, they would have trouble surviving outside the host cell, and trouble penetrating the cell walls of other cells, in order to spread from one host to another.  So perhaps it was the genius of the mitochondria to induce some chemical change that would soften the host’s cell wall, and to promote behaviors that would seek other cells to merge with, giving the mitochondria a chance to spread.

My take: this hypothesis has the virtue of being “conservative” in the sense that it fits well within the predominant selfish gene paradigm.  What could be more selfish than for the mitochondria to want to spread themselves?  But at a slightly deeper level, the main thing that the selfish gene paradigm has going for it is that it is supposed to provide an explicit mechanism for natural selection, i.e., that the gene that makes the most copies of itself is the one that prevails.  In this case, Lane’s hypothesis suffers for want of a mechanism how the mitochondria were able to take control of the cell’s behavior and override the interest of the genes in the nucleus for which sex was a liability.

 

Difference between plants and animals

Mitochondria reproduce within a cell so their DNA is copied many times for each one time that the nuclear DNA is copied.  Furthermore, mitochondria exist in an environment of high-energy chemistry (ROS) that is a constant threat to the integrity of their DNA.  So we expect high mutation rates in mitochondria, perhaps high enough to cause permanent damage and impaired performance.  Somehow, in domesticating its mitochondrial guests, cells had to learn to culture the healthy ones and eliminate the damaged ones.  Otherwise, mitochondria would gradually mutate and degrade over time.

This is a genuine conundrum, about which there are really no cogent ideas in the literature.  If natural selection keeps populations healthy (and even improves them gradually) by filtering out the dysfunctional, where is the selection on mitochondria as they reproduce within a cell?  Most dangerous of all would be the possibility of Darwinian competition within a cell among the different mitochondria.  Some mitochondria might devote less of their metabolisms to serving the host cell and more to reproducing faster than their sisters.  This could produce an evolutionary advantage within the cell for the slackers, the least useful mitochondria.  Selfish evolution of mitochondria is an existential threat to the partnership between mitochondria and host.

Lane devotes a whole chapter to speculation about the resolution of this problem.  We know that nature has managed to keep mitochondria healthy over billions of generations, in all surviving eukaryotes, but we weren’t around to watch how the mitochondria were tamed or convinced to submit to the hegemony of the cell nucleus.  What we have to go on are surviving patterns that may bear the imprint of this ancient battle.  The fact that mitochondria are inherited through the female line only is one piece of data.  A difference in strategy between plants and animals may be another legacy of the battle: any cell of a plant’s meristem can grow into a seed that grows to a new plant, but in animals, the “germ line is segregated”, meaning that there is specialized reproductive tissue, protected from the earliest stage of embryonic development.  Lane relates this difference to the fact that animals have a higher metabolic rate, with more mitochondria that are more active, thus a lower mitochondrial mutation rate.  There may even be a connection to the reason that females lose their fertility earlier than men; the mitochondria become more highly mutated late in life, and it would be a risk to the offspring to launch them into life with a stock of mutated mitochondria.  Males can afford to reproduce later in life because they don’t contribute mitochondria to the offspring.

 

Aging and death

Lane doesn’t have a lot to say about aging in this volume, but he does note that aging only really became an option once the germ line was segregated.  Germ line cells need to have full capacity for regenerating everything (pluripotency) but cells of the soma have the luxury of specializing, and one option is to differentiate and grow once and for all, creating an organ that must last a lifetime (like a brain or heart).

In the end, Lane’s explanation of aging lands at a place very close to conventional theories based on tradeoffs.  The somatic tissues of the body can’t be simultaneously good at everything, and they are specialized to their differentiated purpose, to the detriment of the ability of regenerate.  Hence they are prone to wear out over a lifetime.  I find this explanation less compelling than many of his other ventures, but this is probably inevitable, since evolution of aging is the area where my own thoughts are most highly developed.

Lane goes on to describe his own version of the mitochondrial free radical theory of aging, which is not an evolutionary theory.  He elaborates why, despite the many well-known failures of this theory in its naive form, he nevertheless finds a core of truth in it.

Conjugation of Ciliates

Sex and Death in Protists Presages Sex and Death in Multicelled Plants and Animals

The mechanics of conjugation in protists looks strikingly like the mechanics of sex in later multi-celled organisms.  The way in which the cells merge, the crossover of chromosomes, the particular genes that are involved all point to a close relationship.  Most striking is the strange mechanism of doubling the chromosome population before dividing it in half, and then in half again.  The very arbitrariness of this behavior, and the fact that we see it both in protist conjugation and in male-female sex, is attests to the fact that latter evolved from the former.

I’ve said that sex and reproduction in one-celled eukaryotes are separate, unrelated functions.  But there does exist one connection in ciliates, an advanced group of protists including the paramecium.  Telomeres get shorter and shorter with each cell division.  This is cellular senescence.  It is permitted to continue, threatening the cell’s viability, because telomerase is repressed, and only comes out to restore the telomere when two individuals conjugate.

Thus, already in the early ciliates, cellular senescence has the purpose of enforcing conjugation.  This ancient form of aging evolved to protect population diversity.  And in higher organisms to this day, cellular senescence contributes to the death of the individual, assuring that the population continues to be enriched by new combinations of genes.  The rationing of telomerase in protists presages the rationing of telomerase in you and me.

(William Clark tells this story in his very readable book, A Means to an End.  My current project is a computer model demonstrating how telomerase rationing evolved on this basis.)

Where to go from here?  Two suggestions

I am an enthusiastic supporter of Lane’s program, trying to understand the broad outlines of evolution, and why life is the way it is.  I offer, from my own experience, two more themes that might complement his program.

  • the conflict between what is adaptive for the individual and what is adaptive for the community, and how evolution has ways to suppress individual competition in order to create cohesive communities that are powerful competitors.
  • adaptations at every level from chromosome structure to ecosystem structure that contribute to evolvability.  It seems that natural selection has been a bootstrapping process, constantly increasing its own efficiency in the long term, even as it is selecting higher fitness in the short term.

Suppression of individual competition has been necessary for evolution to be able to find long-term solutions.  This happens in somas that have the same genome as the germ line, and so their allegience to the germ line is not in question, and even in eusocial insects, where close kin selection helps to support division of labor in a functional community at a higher level of organization than the individual soma.  David Sloan Wilson has devoted his career to the theory of multi-level selection, the ways in which natural selection operates simultaneously at the level of the individual and larger units of families, populations, and entire ecosystems.  Often there are conflicts between what is good for the individual and what is good for the community, and the striking thing (taking the large perspective) is how consistently the communal interest has managed to take precedence, suppressing selfishness.

*   *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *    *

 

Lane doesn’t mention “evolvability” by name, and tends to see it as random, chance event.  “Adaptive” is the operant word, which signifies a Darwinian process,

changes to the genome itself, which might take the form of large deletions, duplications, transpositions or abrupt rewiring as a result of regulatory genes being inappropriately switched on or off. But such changes are not adaptive; like endosymbioses, they merely alter the starting point from which selection acts.

But I would suggest that there are too many of these properties of eukaryotic life that seem to serve not the gene or the individual carrying it, but the long-term viability of the community.  We should expand our notion of a “Darwinian” process, if necessary, to accommodate the reality that evolvability has evolved.  To be explicit:  “Fitness” is the ability to survive and reproduce copiously and robustly.  “Evolvability” is the ability to increase in fitness.  Evolvability is the rate of change of fitness.  We all agree that there is natural selection for fitness.  The controversial idea is that there can also be natural selection for its rate of increase.

I have a personal relation to this idea.  Harvard astrophysicist David Layzer wrote the first modern paper proposing the evolution of evolvability in 1980 when I was his student.  Layzer’s analysis was ignored by the biology community for 16 years, until the time was ripe, and the same idea was re-cast into language more familiar to evolutionists by a prominent evolutionary theorist who teamed up with a creative and versatile computer scientist.  Wagner and Altenberg generated a discussion that has developed and expanded to this day, but the revolutionary implications of this idea for evolutionary theory have yet to be assimilated.  When the central importance of evolvability is fully appreciated, I predict that it will alter the foundations of evolutionary science.

Examples of evolvability adaptations include:

  • Sex imposes a huge cost in individual fitness, but promotes evolvability.  In fact, sex has benefits both for evolvability and for expanding the level of selection.  As practiced by eukaryotes, sex gives each gene a stake in survival of the entire breeding community, and thereby promotes cooperation over selfishness [ref]
  • Hierarchical signaling cascades, “command and control” with HOX genes controlling transcription factors and transcription factors controlling expression of many genes at once.
  • Eukaryotic proteins are modular, with modules that are re-used in different combinations for different purposes.  “Exons” are areas of the chromosome that code for pieces of protein.“Why do eukaryotes have genes in pieces? There are a few known benefits. Different proteins can be pieced together from the same gene by differential splicing…”

Though he never uses the word “evolvability”, Lane gets the message clearly about the benefit of sex, “fending off debilitating parasites, as well as adapting to changing environments, and maintaining necessary variation in a population.”  In my view, he has yet to realize the profound implications of the fact the sex evolved for the sake of its contribution not to fitness but to evolvability.  The fact that natural selection can favor not just fitness itself but also the rate at which fitness increases carries a deep message.  “Evolvability” is not an individual trait of immediate value, but a property of an entire breeding community (a deme), spread through evolutionary time.  The implication is that natural selection can enhance collective fitness, not just individual fitness, and that the long-term health of the community can be favored over the short-term advantage of the individual.

Evolvability is both a result and a cause of natural selection for traits (like aging) that benefit the community over the individual, even at a substantial cost to individual fitness.  Evolution of evolvability is a bootstrap, a self-reinforcing process, a positive feedback system.

Sex in particular helps to elevate the level of selection from the individual to the community, because sex gives each gene a stake in survival of the entire breeding community, and thereby promotes cooperation over selfishness [ref].

This is a further clue, a connection between multilevel selection and evolvability.

 

Epilogue

I am full of admiration for Lane’s ambition to explain the broad properties of eukaryotic life, and he has made impressive progress pulling together diverse evidence into coherent theories.  Lane is a biochemist and a “strict constructionist”, working within the predominant school of evolutionary theory, sometimes called the “New Synthesis” or “Population Genetics” or “neo-Darwinism”.  My opinion is that to make further progress, he will find it necessary to venture beyond the neo-Darwinian framework to think about levels of selection, evolvability, and evolutionary ecology.

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GDF11—Not So Fast

A research report from Novartis may temper our excitement about GDF11, which was a runner-up for Science Magazine’s 2014 Breakthrough Of the Year.

Bakground

“Heterochronic parabiosis” is the sanitized word for sewing together as Siamese twins two animals of the same species but different ages.  Modern implementation as a research technique was pioneered by Clive McCay in the 1950s, the same McCay who brought us caloric restriction in the 1930s.

The two animals share a common pool fo blood.  What is clear is that the older animal in the pair benefits from young blood.  Healing is improved, and some tissues are rejuvenated.  What is less clear:  what are the elements in the blood that are responsible for the rejuvenation?  Is there a “youth serum”, transferred from the young animal to the old; or in fact is there a blood factor responsible for deterioration, and the old animal is benefiting from dilution of his elder toxins?  Are there a few such blood factors, or too many to form the basis of a practical therapy?

In the last ten years, there has been a diaspora of researchers from the Stanford lab of Tom Rando, young researchers now at Berkeley and Harvard who are pursuing advanced techniques of blood transfer, seeking to isolate the active ingredients.  A consensus is emerging that

  • It is not the red or white blood cells, but dissolved proteins in the blood that make the difference.
  • There are both pro-aging and anti-aging factors in the blood.

The big questions remaining:

  • There are at least several factors of each kind, pro- and anti-aging.  Is the number of essential blood factors small and manageable, so we might hope to make a “bloody Mary” cocktail?  Or is the number so large this is impractical?
  • Will these blood factors reboot the body’s epigenetics so the old body starts producing the young mix itself?  How long must the body be exposed to the young mix before it starts to produce the young mix itself?

Last year in particular saw eye-popping results from the Berkeley lab of Irina and Mike Conboy, and from the Harvard lab of Amy Wagers.  The Conboys claimed that oxytocin is a blood factor promoting longevity.  [ref, my blog]  Wagers identified GDF11 as a blood factor that declines with age, and enhances strength and endurance when administered to muscle tissue in mice.  [ref, my blog]  In humans, GDF11 has been shown to increase nerve growth.

 

Cousins of GDF11

A rejuvenating role for GDF11 was a surprise because it is in the TGFβ class of hormones, which generally have negative effects on muscles.  In a 2013 blog, I identified TGFβ as one of the blood factors that we have too much of as we age.  Myostatin is the best-known member of this group, and it inhibits muscle growth.  Mice lacking the myostatin gene grow double-size muscles and have better insulin sensitivity.  Creatine is a myostatin inhibitor that is popular among muscle-builders.

Genes for GDF11 and for myostatin are 90% identical.  But mice lacking GDF11 don’t have bigger muscles, and in fact they die soon after birth.  So it’s possible that GDF11 is good and myostatin is bad.

 

The latest news

Last week, David Glass and a team at Novartis report that they have failed to reproduce Wagers’s results about GDF11.  From a Nature News report by Sara Reardon:

Glass and his colleagues set out to determine why GDF11 had this apparent effect.  First, they tested the antibodies and other reagents that Wagers’ group had used to measure GDF11 levels, and found that these chemicals could not distinguish between myostatin and GDF11. When the Novartis team used a more specific reagent to measure GDF11 levels in the blood of both rats and humans, they found that GDF11 levels actually increased with age — just as levels of myostatin do. That contradicts what Wagers’ group had found.

Glass’s team next used a combination of chemicals to injure a mouse’s skeletal muscles, and then regularly injected the animal with three times as much GDF11 as Wagers and her team had used. Rather than regenerating the muscle, Glass found, GDF11 seemed to make the damage worse by inhibiting the muscles’ ability to repair themselves. He and his colleagues report their results on 19 May in Cell Metabolism.

Woops.  The Wagers results may prove to be an error, or it may be that the story is more nuanced.  It would not be surprising if there is such a thing as too little GDF11 and too much GDF11.

Wagers, however, stands by her findings. She says that although at first glance the Novartis group’s data seem to conflict with her team’s results, there could be multiple forms of GDF11 and that perhaps only one decreases with age. Both papers suggest that having either too much or too little GDF11 could be harmful, she says. She adds that the Novartis group injured the muscle more extensively and then treated it with more GDF11 than her group had done, so the results may not be directly comparable.

 “We look forward to addressing the differences in the studies with additional data very soon,” Wagers says.

Rando expects that researchers will now investigate the finding2 that GDF11 affects the growth of neurons and blood vessels in the brain. “I’m not sure which result is going to stand the test of time,” he says.

Two Unrelated Items of Interest

Life Extension magazine for June claims that fear of Testosterone has been unwarranted, that the benefits of T for strength and heart health do not come at a cost in increased cancer risk or decreased longevity.  (June edition is not yet on-line at LEF, but has been uploaded to Dropbox by a colleague here.)

Low endogenous bioavailable testosterone levels have been shown to be associated with higher rates of all cause and cardiovascular-related mortality…

Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin A1c in diabetics and to lower the BMI in obese patients. These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.


Here is an intriguing news release from Yale about a protein found only in primates that is useful for making ordinary cells into stem cells.

 

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