Nutritional Geometry 2: Carb Restriction

Last week’s focus was the evidence in favor of a low-protein diet.  In this context, high-carb diets came out on top.  But there is also evidence that for the average denizen of the developed world who does not restrict protein, there are dangers in a diet based on staple carbohydrates, especially sugars and simple starches that pass quickly from the stomach to raise blood sugar.

Beginning in the 1970s, health literature convinced Americans to avoid fatty foods, and the processed food industry was eager to oblige, advertising “low fat”, while adding more sugar to make foods tasty, and taking advantage of a new, efficient chemical process that made high-fructose corn syrup cheaper than sugar.  But as we substituted carbs for fat, we became obese and diabetic.  Metabolic syndrome and Type 2 diabetes were new terms added to the medical lexicon to describe what was ailing us.  Gary Taubes was first to hypothesize a causal relationship:  Our high-carb diet was leading to insulin resistance (which promotes weight gain) and weight gain (which promotes insulin resistance)—a vicious cycle that he first wrote about in the 1990s.

  • Diets that are high in fat, low in carbs, are an effective way to lose weight, at least in the short term.  Herman Taller, Robert Atkins, and Barry Sears taught this truth to three successive generations of Americans.
  • In animal experiments, insulin and its cousin IGF-1 are the hormones that mediate the connection between more food and shorter life.
  • Blood sugar levels rise with age, and in people with genes for exceptional longevity, the rise happens more slowly.  Blood sugar levels are a risk factor for mortality.  So how much of a stretch is it, really, to say that the rise in blood sugar with age contributes to risk for the diseases of old age?


The case against carbohydrates comes right out of mainstream practice for diabetes, but it has also been treated as a fringe fad when David Perlmutter stretched the case to make a point in a series of bestselling books.  In Grain Brain, Perlmutter pounds home the association between high blood sugar and all the diseases of old age, but most especially dementia.  (Vascular dementia to a greater extent than Alzheimer’s disease.)

The combination of biochemistry with population data associating carb intake with metabolic syndrome has convinced many people that a carbohydrate-based diet is a hazzard.  But it’s a difficult case to prove, because humans don’t take well to living in cages, and because epidemiological studies of human aging require decades.  In reading this week, I’ve discovered just how contentious is the whole subject of low-carb vs low-fat diets. Many such deeply divisive questions about health can be traced to corporate interests on one side, but this one may be academic, with ambiguous data, no long-term results, and different individual responses that are seen through different theoretical lenses.

Although bottom-line questions about mortality and life expectancy may be difficult to address in human studies, we might hope for an answer to the question: Do people whose diets have a lower glycemic index have a lower risk of metabolic syndrome?  The best study I’ve been able to find on this question [2004] associates insulin resistance with dietary factors in 2,800 sons and daughters of the original Framingham heart study.

After adjustment for potential confounding variables, intakes of total dietary fiber, cereal fiber, fruit fiber, and whole grains were inversely associated, whereas glycemic index and glycemic load were positively associated with [insulin resistance]. The prevalence of metabolic syndrome was significantly lower among those in the highest quintile of cereal fiber and whole-grain intakes relative to those in the lowest quintile category after adjustment for confounding lifestyle and dietary factors. Conversely, the prevalence of metabolic syndrome was significantly higher among individuals in the highest relative to the lowest quintile category of glycemic index.

Fruits and whole grains were found to provide protection against insulin resistance, despite the fact that they are primary carb sources.  Presumably, it is only sugar and simple carbs (white flour, rice, potatoes) that add to risk of insulin resistance.

A South African doctor collected stories from patients who, by and large, were very satisfied with the results of switching to a low-carb, high-fat diet. Almost all lost weight.  Some claimed that their diabetes was “cured”.

In this study, people lost weight on a six-month program of either restricted fat or restricted carbs.  But people who were already insulin-resistant did a little better on the low carb diet, while those who still retained insulin sensitivity lost more on the low fat diet.

This study put obese subjects with metabolic syndrome on either a low-fat or low-carb diet for six months.  Both groups lost weight and gained insulin sensitivity, on average.  The low-carb group lost more weight and gained more insulin sensitivity.  However, there was a lot of variation within the groups.

Insulin resistance is associated with diabetes and heart disease, both independently and as part of metabolic syndrome. Exercise has a strong beneficial effect and obesity a strong adverse effect. The balance of evidence suggests that a high-fat diet is likely to reduce insulin sensitivity but the effects of dietary carbohydrates are more controversial. Extensive studies in animals showed a detrimental effect of diets very high in fructose or sucrose, particularly in association with induction of hypertriglyceridemia. The more limited studies in humans had conflicting results, partly because of heterogeneity of design. Certain groups of subjects may be more sensitive to adverse effects of high intakes of dietary sucrose or fructose. [ref]

In other words, “There is conflicting evidence concerning the influence of total carbohydrate intake on insulin sensitivity.”

Two NIH studies [one, two] by Kevin Hall just this year compared short-term effects on metabolism from carb and fat restriction.  They put people in metabolic chambers to measure CO2 and H2O in their respiration, in order to calculate how much fat was being burned.  Hall claims that the results disprove the insulin theory of weight loss.  But to me the results seem puzzling and inconclusive.  They claim to calculate that the short-term weight loss from carb restriction is loss of muscle, not fat.  This is disturbing, if true.  The metabolic calculations are based on isotope labeling and other sophisticated technologies.  I trust the chemistry, but I tend to skepticism based on the fact that once in the body, labeled water gets mixed to an unknown extent with ubiquitous body water.  Short-term studies with sophisticated metabolomic measurements might tell us a good deal about the body’s biochemistry, but still leave us wondering about long-term accommodations of hormonal balance, energy metabolism, and gut biota.

Past positive results from low-carb diets, Hall says, are probably about “compliance” and not metabolism.  “Compliance” is our ability to stick with a diet, and, IMHO, this should not be separated out as some kind of soft, psychological confounder.  It may well be that the whole advantage of a high fat diet is that those people for whom it works—not everyone—feel less hunger and more sustained energy, and that may well be linked to insulin cycling.

What can we conclude but that we’re each on our own, and we have to find the diet that works best for us as individuals?  And that that our dietary needs may change with age, so repeating the self-experimentation at least once a decade is helpful.  In experimenting on yourself, keeping weight off is probably as good a measure as any of how well your body is responding.
Glycemic index and glycemic load

Glycemic index is about how quickly the carbohydrates in a particular food enter the bloodstream.  Glycemic load also takes into account how much carbohydrate the food contains, and also a guess at portion size.  Here’s a chart from Harvard Med School with glycemic index and glycemic loads for 100 “common foods” (some more common than others).  Much of the chart is predictable—cakes and sodas look bad, beans and nuts look good.  There are a few good surprises, and a few bad ones.  (Note that the GL listed for oranges =45 is almost certainly a mistake.  It should be 5 or 6.)

Good Surprises         GL Bad Surprises              GL
Premium Ice Cream 3 Cornflakes 20
Watermelon 4 Ocean Spray Cranberry Juice 24`
Apple 4 Pasta 26
Peanut M&Ms 7 Raisins 28
Whole Wheat bread 8 Baked potato 33
Regular ice cream 9

The ranking by glycemic load is appropriate if you are trying to minimize total insulin burden.  But if you are aiming for a low-protein, high-carb diet as described last week, then you are interested in glycemic index (because you want high-carb foods that don’t trigger insulin release).  The catch (for protein restricters) is that most foods with low GI are protein sources.  Which foods offer a combination of low protein and high carb without the insulin trigger?  Grapefruit stands out, apples, pears and other fruits will be preferred carb sources.  Some kinds of brown rice are more equal than others, while potatoes will be avoided because of too high a GI, while whole wheat and corn will be taken in moderation because they have too much protein.


Fructose, Glucose, Sucrose

So lotsa fruit seems to be the answer…until we introduce one more wrinkle.  Fruit contains fructose, and there is a school of thought that says fructose is much worse for you than glucose.

There are two simple 6-carbon sugars, fructose and glucose, and table sugar=sucrose is a loose binding of one fructose with one glucose.

Fructose and glucose are both sweet, and they’re often found together in fruits.  Apples and pears have a lot more fructose than glucose, while bananas, peaches and sweet potatoes have a little more glucose than fructose.  Honey has more fructose than table sugar.

Starch is a polymer of glucose.  It is quickly broken down (beginning in the mouth) into glucose molecules, so starchy foods have a high glycemic index.  But starch is all glucose, no fructose.


Glucose and fructose may be chemical cousins, but the body treats them quite differently in the short term.

  • Glucose is fuel, usable right away.  When you eat enough for your activity level, glucose is absorbed right into the blood, and it is consumed promptly.  When you eat more glucose than you can burn, insulin is secreted, signaling the liver to remove some glucose and turn it to glycogen.  The liver stores about a day’s supply of glycogen to be drawn on as necessary, and glucose in excess of that is turned to triglycerides, a form convenient for storing energy in fat cells.
  • Fructose is also absorbed promptly from the stomach into the bloodstream, but it is removed immediately by the liver, turned directly to triglycerides.  No insulin is involved.

The short-term metabolism of fructose and glucose is well characterized, but you and I are interested in the long-term consequences of eating fruits high in fructose compared to starches which are quickly metabolized to glucose.  This turns out to be a controversial topic.

In recent years, Robert Lustig and Richard Johnson have argued that foods with more fructose than glucose lead quickly to insulin resistance.  They blame soaring rates of obesity and metabolic syndrome=type 2 diabetes on the invention of a process for producing sugar from corn starch that is cheaper than cane sugar.  The “high-fructose corn syrup” that results happens to be 55% fructose.

Yes, fructose has a low glycaemic index of 19, because it doesn’t increase blood glucose. It’s fructose, for goodness sake. It increases blood fructose, which is way worse. Fructose causes seven times as much cell damage as does glucose, because it binds to cellular proteins seven times faster; and it releases 100 times the number of oxygen radicals (such as hydrogen peroxide, which kills everything in sight). Indeed, a 20oz soda results in a serum fructose concentration of six micromolar, enough to do major arterial and pancreatic damage. Glycaemic index is a canard; and fructose makes it so. Because fructose’s poisonous effects have nothing to do with glycaemic index; they are beyond glycaemic index. [Lustig writing in The Guardian]

I’m not so impressed with the “seven times faster”, because fructose doesn’t remain long in the bloodstream, and I’m not so concerned about free radicals because (as I’ve written) they are as likely to increase our life expectancy as to decrease it.  Lustig also writes that because fructose tastes so good and bypasses insulin and blood sugar, it undermines the satiety response and leads to compulsive eating.  But the most complelling claim here is about the loss of insulin sensitivity, which I regard as a hallmark of aging.  Is fructose really worse for insulin resistance than glucose?  Lustig says YES, and his theory is articulated here.  Lustig makes his case by reasoning about biochemistry in the liver.  But what about real evidence in real people?  In short-term studies, substitution of fructose for glucose in the diet shows no sign of increasing insulin resistance; on the other hand, there is a well-known correlation between consumption of high-fructose corn syrup with metabolic disease.

What Lustig comes to beneath the headlines is, “the dose makes the poison”; and I think this is a healthy attitude for all of us.  Drinking sugared beverages and eating (more than occasionally) foods sweetened with high-fructose corn syrup damages insulin sensitivity.  At the other end, eating a few pieces of fruit during the day can be part of many diet plans that work well for health and longevity.  Those are the easy cases.  In between we have the more difficult case of the semi-fructarian.  That would be me.  I get most of my carbs from fruit, and I avoid starch (rice, potatoes, bread, pasta).  I maintain weight with exercise and portion control, I eat leafy greens every day and I get a ton of fiber, and though my protein intake is high compared to last week’s ideal (~60g/day), it’s all vegetable protein.  Would I be better off if I backed off from my fruit consumption and substituted whole wheat bread and other complex carbohydrates?  It’s an experiment that I might try next winter—but not in September when every kind of delicious fruit is fresh and abundant.

In any case, there is a consensus view that moderate fructose is part of a healthy diet, and that excessive fructose exacerbates the ill effects of a sugary diet [ref, ref, ref, ref, ref, ref, ref].  After reading all these articles (well…reading all the abstracts and some of the content underneath), I’m not convinced one way or the other about fruits (glucose+fructose) vs grains (glucose only, from starch).


Insulin resistance is tied to high blood sugar

Metabolic syndrome, including the “normal” version that comes with aging, is characterized by failure to respond to insulin, leading to both higher insulin levels and higher blood sugar.  Is it the higher insulin level or the higher blood sugar that is responsible for the damage?  YES.

Insulin signaling speeds up the rate of aging.  Sugar in the blood reacts with proteins to create cross links (glycation) that prevents the protein from folding properly.  (Fructose is more prone to this reaction than glucose, but fructose does not stay in the blood so long.)  Type I diabetics have no insulin, and if their insulin injections are not carefully regulated, they are at risk for blindness and nerve damage in the extremities, both from high blood sugar.  So, with metabolic syndrome, both the insulin levels and high blood sugar pose risks.  The proper medical terminology for this situation is “double whammy”.

So both high insulin and high blood sugar are bad for us.  With the separation of fructose from glucose, we have the possibility of coupling lower insulin levels with higher blood sugar. Is the tradeoff worthwhile? Is fructose the optimal low glycemic index sweetener?

And in the end…

You have every right to ask where I’m going to come down on these questions after a post that is longer and fuller of ambiguities than the usual.  I’m going to disappoint you. It’s clear to me

  • that excessive sugar, both glucose and fructose, is bad for most everyone
  • that high fiber is good in a lot of ways
  • that different metabolisms respond differently to low-carb and low-fat diets.
  • that weight control is a good way to tell if a diet is working for you

It leaves me counseling personal experimentation, which is what I always say anyway.

There is a phenomenal amount of individual variability in energy expenditure, both resting and total.   Measured across two weeks, one person had total EE  almost 800 cal/day above their baseline while another had a EE almost 1200 cal/day below baseline.  That’s huge.  I imagine that the individual whose resting EE declined by almost 500 cal/day will be having a tougher time maintaining his/her weight loss than those lucky few who saw increases. [from a pro-carb blogger]


A simple program for weight loss and life extension

Before each time that you eat, do 1 to 2 minutes of exercise, intense enough to leave you panting and drink a pint of water.  The result is to suppress the sugar and insulin spikes that follow a meal, and to burn more of the food energy, store less as fat.

Next week, part 3: Specifics on the high-fat, ketogenic diet

Nutritional Geometry

We all know that the less we eat, the longer we live, and that periods of fasting, long and short, can also trigger a longevity dividend. What about macronutrient proportionsprotein, carbohydrates, and fat? The argument for carb restriction is that it helps keep insulin signaling down, and slows the inevitable advance of metabolic syndrome. The argument for protein restriction is that animals on protein restricted diets have sometimes been found to live longer, independent of total calorie intake. The argument for fat restriction is that mice on a high-fat diet have shortened lifespans compared to either high-carb or high-protein. So, what macronutrient proportions are best for people, or does it matter at all? I have advocated the carb restriction diet in the past, but today I’m considering the evidence for protein restriction, and speculating on the possibility we might be able to do both.

Nutritional Geometry is a 9-year-old Australian approach to macronutrient proportions which has been honing its message more recently [ref, ref, ref]. The topic has provided fodder for research grants (and for bloggers) because it is rich with nuance and resists generalization.

If you are looking for bottom-line advice, I’d say:

  • High-fluid, high fiber content are consistent recommendationsno tradeoffs, no qualifications. Leafy greens rule!
  • Low-protein when you’re young, higher protein when you’re old
  • Vegetable protein is preferable to meat or dairy
  • If you’re game to try something new, a high-fat ketogenic diet may offer advantages.

But the subtleties are interesting and worth exploring, and (as always) the best diet for you is the one you can live with.

Last year, the Australian group published a study in which they fed mice on 25 different diets, differing in protein, fat, carbohydrate, and energy density. The main result from this study is that mice fed a low protein, high carb diet lived longest, though they ate more food—presumably because they sensed that they were not getting enough protein. At the lowest protein concentrations, their total protein was still low, even though they ate more food, and they lived longer, even though they ate more food. For mice, a low-protein chow led to more eating and a longer life. The trick worked for low protein, high carb diets but not for low protein, high fat diets. In this case, the mice ate so much more food that they became obese and their lifespans were shorter. The optimum diet for female mice had an 11:1 ratio of carbohydrate to protein, and for male mice, 13:1.

If we extrapolate to humans, the message would be that for people who prefer not to restrict their portions, a very low protein diet provides a path to a longer life. But this is a dubious extrapolation. The mice were given no choice of chow. (There were 25 different formulations, but only one available to each cage of mice.)  People, in contrast, have a dizzying choice of foods. I know the feeling of having had my fill of fruit, and though not feeling really hungry, craving protein nevertheless. Humans are not at all comparable to lab mice in this regard.

A balanced diet?

A balanced diet?

I wonder for how many people a diet restricted to foods that have carb:protein ~ 12 to 1 is realistic. Here is a list of foods with carb:protein ratios [from USDA web site]:

protein2carb-ratiosConclusion: To get the low protein diet of the mouse experiment, you’d probably have to be a fructarian.

I was surprised to see that the study reported no benefit from a high-fiber diet.

Reduction in calorie intake was achieved by diluting the food with nondigestible cellulose, which allows ad libitum feeding but restricts total energy intake when compensation for dilution by increasing food intake is incomplete. Mice fed experimental diets containing 50% nondigestible cellulose ate a greater bulk of food (3.6 vs 2.5 g/day) but ingested about 30% less total energy than mice provided with food containing higher energy content (30 vs 42 kJ/day). Therefore, these mice had a reduction in energy intake similar to those reported in nearly all other studies of calorie restriction in which access to food was restricted… When corrected for lean body mass, the hazard ratio for death was not influenced by calorie intake, except at the highest energy intakes, which were achieved only by low-protein, high-fat diets.

Fiber in the chow filled the mice up, causing them to eat less calories (though more bulk) than they would have otherwise. But did they live longer? Yes, they did, though you might not get it from the language used here. Lifespan was not increased by lower calories “when corrected for lean body mass”, but whem mice are on a lifelong low-calorie diet, they don’t grow as large, so their lean body mass is smaller. Correction “for lean body mass” is generally not the way data is reported in these experiments. So the result here is not necessarily inconsistent with the great body of experimental results that say lifelong caloric restriction leads to longer lifespan.

Most interesting is the last caveat: The problem with high fat diets is that mice overeat, become obese and have shortened lifespans. But with both high fiber and high fat, the mice tended not to overeat, and their lifespans were enhanced.

This may suggest a practical diet strategy for humans. Mice on a high-fat diet ate a lot more calories, and similarly some people find deep fried foods and milk shakes tempt them to eat too much. But for those with the willpower to interrupt a high-fat meal, they may find that they don’t get hungry for several hours afterward. This is because fat is slower to be digested than either protein or (especially) carb. High-carb meals lead to a fast rise in blood sugar, then an insulin spike that makes blood sugar plummet, triggering hunger. After a high-fat meal, hunger is much slower to return.

High-fat meals lead mice to obesity and short lifespans because they overeat. Extra fiber in the food helps them to regulate their intake. If this works for humans, there is the possibility that a high-fat, high-fiber diet can offer the advantages of both protein restriction and low insulin. I’ll go into this option in depth next week.
Protein: How low can you go?

The biggest issue is maintaining muscle mass, which is crucial to vitality and wellbeing, and becomes a protective factor from mortality as we get older. We have all seen pictures of starving African children with bloated bellies. They are not actually suffering from insufficient calories, but insufficient protein. Their largest muscle, in the abdomen, has beeen deprived of protein so long it has lost all its tone.

Both Pederson and Rand (2013) recommend about 0.85g protein for each Kg of body weight. For a 160-pound man that’s 61g, and for a 125-pound woman, 47g of protein daily. Pederson found that all the diseases of old age are statistically associated with higher protein intake. More general sources quote a slightly lower 0.8g/Kg.

These numbers are only an average over many populations in many studies. Your body might need a lot more or a lot less protein than this, and your best indication is to monitor your energy level, your weight, your muscle mass, and blood analysis as you experiment with different diets.

In this study [2007] of Swedish women 30-49, those in the highest decile of protein consumption died at a rate 20% higher than those with the lowest decile. But mortality rates are low through that age range, and what is more important is the effect on health and mortality in the long term.


Animal vs vegetable protein

In a literature review, Pederson (2013) found links between animal protein intake and various mortality factors, but vegetable protein was either beneficial or neutral. Surprisingly, it is the high-protein diets that are associated with type-2 diabetes, not the high-carb diets. But this conclusion seems limited to animal sources.

This study [2012] from Harvard School of Public Health found a 13% increase in mortality for every daily meal at which red meat was consumed, rising to 20% for processed meats, corresponding to 2 to 3 years of extra life.

Seventh Day Adventists are, as a group, health- and diet-conscious, and they live longer. Their religion tells them not to eat meat, but many do anyway. Seventh Day Adventists who are vegetarian live 3 years longer than Seventh Day Adventists who eat meat.

How does the body know animal from vegetable protein? I have seen no theories on this. Animal protein is generally higher in methionine, but methionine restriction only lowers mortality when methionine intake is very low–probably not the case generally in any of these studies. It could be the saturated fat that accompanies the protein; or it could be hormones that are present in all animals, with higher levels in commercial meat; or it could be an effect mediated through the effect on intestinal flora. But my best guess is that it has to do with heightened inflammation from a low-level immune response to chronic exposure to alien animal proteins.


More protein as you get older

My favorite authority on this and other questions of diet is Valter Longo and his group at University of Southern California. In their 2014 review, they found a dividing line at age 65. Younger than 65, higher protein intake was associated with higher mortality, and older than 65, higher protein intake was associated with lower mortality. As in other studies, the damage was only visible for animal protein, and disappeared into the noise for vegetable protein.

Frailty is an issue in older adults., and greater muscle mass can support a more vigorous exercise regimen. This is a plausible reason for the increased protein need with advanced age. Longo also talks about IGF-1 signaling. IGF stands for “insulin-like growth factor”, and it is a hormone we need when we are young, but which increases mortality when we are older. Lower protein is associated with lower IGF-1, though the statistical association falls short of suggesting that this is the reason that low protein is beneficial.

This is the best article I have found on the subject of increasing protein need with age, but still it is not really what I’d like to see. Mortality in young people is not the best measure of whether a low protein diet is beneficial, because mortality in young people is still low, and even a temporary doubling of mortality make little difference. What we really want to know is how protein in the diet of young people affects their life expectancy when they get older. This is a study that has not yet been done, probably because it involves following a large population for a long period of time (like the Framingham Heart Study and the Whitehall Study in Britain, but these did not address protein.)
Roughage = Dietary Fiber

Everyone agrees that fiber in the diet has a large benefit for gut health and especially for preventing colorectal cancer. I have speculated that the benefit goes beyond this. A high-fiber diet is a calorie restriction program in itself. Fill your belly with fiber, and it you feel full with fewer calories. An ultra-high fiber diet pushes food through your digestive tract faster, so you absorb less of it. Fat is adsorbed on the fiber, and less of it makes it into your metabolism. High fiber in the gut encourages a microbial ecology that affords you less calories.

I speculate based on personal experience, but there is also some literature touching on the subject [ref, ref, ref]. “There was a considerable variability in digestibility of fiber components between individuals.”

Does fiber prevent the absorption of vitamins and other micronutrients as well? Maybe. I haven’t seen literature on the topic, but it makes sense that cellulose adsorbs a variety of molecules that are carried through the intestine undigested. Best to take your supplements separate from your fiber.

I am out on a limb recommending an ultra-high-fiber diet, and I suspect that results will vary widely among individuals. But what is not controversial is the health value of leafy green vegetables—the more the merrier.

Conclusions so far:

This much is clear: Green vegetables are good.  Animal protein is bad.

Beyond that, we might be tempted to interpret the Nutritional Geometry literature to say that “carbs are ok”.  I am wary of this conclusion, however.  It’s not just the standard warning that “mice are not people”. The benefits of a high-carb diet have only been shown in the context of severe protein restriction that I think is unrealistic for most of us. To be continued…

Next week: Metabolic Syndrome, Glycemic Load and The ketogenic Diet

Nobody Dies of Arthritis

directly.  But in practice, the pain of arthritis limits activity and discourages exercise.  The chronic pain of arthritis wears people down, contributing to depression, which is a substantial mortality risk factor.  Limitations on mobility combined with disspiriting effects of pain can destroy the will to live.  There is no cure for arthritis yet, but anti-inflammatories can slow its progress, and one Swiss company claims a cure in the pipeline.

The “commonsense” view of osteoarthritis is that the cartilage that lubricates our joints gradually wears down over time, and when we are old, bone grinds against bone.  Ouch!  In fact, the commonsense view became the medical view which dominated for many years.  But is it really so commonsensical?  Wearing down of the lubricant cartrilage takes place in the course of hours and days, and, in young people, it is rebuilt and replaced as fast as it is worn away.  (Even the association of extreme exertion with early-onset arthritis (Sandy Koufax’s elbow, : Shaquille O’Neal’s foot) is an effect of chronic inflammation rather than physical wear.)  Thirty-year-olds don’t have more arthritis than ten-year olds, but by sixty, almost everyone has symptoms of enlarged joints, degenerated disks or lumbar pain.  What happens over decades is not explained by the sum of tiny deficits in repair from day to day.  Rather it is changes in the metabolism (initiated by epigenetics, and mediated by signal molecules in the blood) that causes a slowing of regeneration and an acceleration of inflammatory damage.

Historically, the medical community distinguishes rheumatoid arthritis–an autoimmune disease–from osteoarthritis, which is accumulated wear on joints.  The emerging view, however, is that there is no fundamental distinction between them, and that the same metabolic forces are at play in both.  The symptoms were always the same, but the distinction was based etiology: osteoarthritis is almost universal in older people, whereas rheumatoid arthritis is traceable to trauma or an autoimmune condition.  We know now that autoimmunity is part of human aging, an icon of the self-destruction program coded in our genes.

Spinal stenosis is a particularly painful and debilitating complication of arthritis in the spine.  Inflamed bone grows until it impinges on the spinal cord, generating numbness or referred pain in the legs and compromising movement.  Fibromyalgia seems to be a generalized inflammation of joints and muscles.


What can be done?

Exercise may be the best treatment.  The cruel paradox is that arthritis makes exercise much less appealing, and so a vicious cycle begins.

“Patients’ fear for disease aggravation and an indefensible traditional approach of rheumatology health professionals to recommend exercise restriction may account for the inactive lifestyle of this population. It is now established that well-designed physical exercise programmes promote prolonged improvements without inducing harmful effects on disease activity and joint damage.” [ref]

Exercise may hurt, but you won’t hurt yourself with exercise.  Cycling and water aerobics are often suggested, not because they are inherently better for arthritis, but because people experience less discomfort and are more likely to stick with the program.

There is no cure for arthritis, but all the emerging anti-aging technologies are expected to slow or turn back the arthritis clock.

I’ve recommended vitamin D for many reasons, especially lowering risk of cancer and preserving the immune system.  In this study, vitamin D supplementation lowered incidence of arthritis by 1/3.  This study found that people with high circulating levels of vitamin D in the blood had risk of arthritis lower by 2/3.  Depending on your metabolism, you may need to take jumbo doses of vitamin D (10,000 – 30,000 IU) to get your blood level up above 90, which I think is ideal. (Here’s a study that looked for a protective effect of vitamin D and didn’t find any. Here’s another study that finds more tentative evidence of a benefit from high blod levels of vitamin D.)

Arthritis may also be one more reason to keep your magnesium intake high.

Glucosamine supplements have been used for more than 20 years, and are well-researched.  On average, they are marginally effective, if taken in sufficient quantity of 3 or more g per day.  Response varies with the individual, and glucosamine is well worth trying.  One study has found a lower all-cause mortality rate in people who take glucosamine.

A dark horse worth trying is boron, a trace mineral for which there is indirect evidence for a powerful benefit [ref].

S-adenasyl methionine (SAMe) is a pro-hormone, sold by prescription in Europe, where it is used as a treatment for arthritis.  Here’s a study that found SAMe worked as well as Celebrex.  My opinion is that SAMe is worth trying, despite thin evidence, because side-effects of SAMe are likely to be salutory.

A study with krill oil produced the best reported results.  Over the first month of treatment with 300mg/day, patients reported substantially less pain and more mobility, and their subjective experience was corroborated by a 30% drop in C-Reactive Protein (CRP) in their blood (a marker of inflammation).

Boswellia is a resin from the sap of a tree, classically known as frankincense.  It is well-known for anti-inflammatory effect, and there are four well-controlled studies that show objective and subjective benefits [1, 2, 3, 4].  (References collected by

Curcumin (from turmeric) is the best known of the herbal anti-inflammatories.  In clinical trials, it has been found to be effective, but not a magic bullet, comparable in benefit to ibuprofen.  Getting an adequate dose absorbed into the bloodstream is always an issue.

Nigella sativa produced benefits for some patients.  It is a tasty black seed, used in rye bread and middle-eastern cooking, known variously as charnoushka, kalonji, or black cumin seed (no relation to cumin).

Here is a review of many herbal anti-inflammatories, with explanation of the role of the signaling by NFkB as a bad actor.  (Full text available from ResearchGate.)  This team of distinguished Indian-Americans, with thousands of publications among them, highlights curcumin, resveratrol, tea polyphenols, genistein (soy), quercetin (onions), silymarin, guggulsterone  boswellia and ashwagandha.  Here is their table, including other candidates that have shown some promise in at least one study.




NSAIDs are effective.  Aspirin and ibuprofen are safe but of small benefit.  COX2 inhibitors (e.g. Celebrex=celecoxib)  are more effective but raise the risk of heart disease.  For some, the tradeoff may be worthwhile.  Celebrex has been marketed by Pfizer for about 20 years, and has been the subject of commercial law suits unrelated to safety.

Steroids (esp dexamethasone) work temporarily and make you feel good for awhile, but are not a long-term solution because of side-effects from upset stomach to diabetes to depression.

Humira, Remicade, and Enbrel are more recent entries into the arthritis marketplace.  They all target tumor necrosis factor (TNF) cytokines, they are all fantastically expensive, and clinical data is yet thin.  Talk to your insurance company.


On the horizon

Two years ago, there was a report from a Swiss pharmaceutical claiming a cure for arthritis in mice.  They combined dexamethasone with targeted immunotherapy, paradoxically using the immune system itself to attack inflamed sites [ref].  Interleukin4 is fantastically expensive, probably one motive for modifying the molecule with an antibody that would seek out inflamed target cells, so the dose can be reduced.  (Of course, lowered dosage also means fewer side-effects.)  The journal article and news reports from 2014 indicated that trials in humans were imminent, but I have been unable to find evidence that this has come to fruition yet.  While you’re waiting, you might write to scientists at ETH, which is a sort of Swiss MIT.


The Bottom Line

As with so many aging conditions, there is no miracle cure, but there are lots of possibilities for treatments that have great benefit for a few, and small benefit for others.  Until we have personalized medicine based on your genetic and epigenetic profile, there is no substitute for personal experimentation.  Many of the recommendations above have beneficial side-effects, or none.  Try them freely, singly or in pairs.  On for a month – off for a month – on for a month – off for a month, keeping a diary of symptoms.  This is a time-consuming exercise, to be sure, but the potential benefit is huge.  Don’t give up if the first few treatments that you try don’t seem to be working; that’s all in the nature of the game.  We’re looking for the treatment that resonates with your metabolism, and you’ll know it when you find it if you can remain objective and scientific.  (That’s the purpose of the diary.)

Social Correlates of Longevity—Part II

When we think about things we can do to have longer, healthier lives, it’s the metabolism that comes to mind—diet, exercise, supplements.  It’s a surprising fact that (at least until the next generation of anti-aging technology becomes available) the most effective things we can do are not just psychological—they’re social.  Perhaps because we were raised in the most pathologically individualistic culture in the history of humanity, this seems hard to take in.  The message is to embed in your community and your family, to actualize your creative potential, to love the people around you, to celebrate life and connect, only connect*.

Philosophers from Kant to Buber like to distinguish two ways that people may relate to one another.  One is utilitarian, using the person to help you make money or obtain something else that you want.  This kind of relationship needn’t be sinister.  There can be cooperation and mutual benefit, but the relationship is a calculated investment for personal gain.  The second kind of relationship is a core of human friendship or love or companionship or empathy that we value for its own sake, independent of whether we can get anything out of it.

Kant (paraphrased by Popper) said, “Always recognize that human individuals are ends, and do not use them as means to your end.”  Buber said, “If I face a human being as my Thou, and say the primary word I-Thou to him, he is not…He or She, bounded from every other He and She, a specific point in space and time within the net of the world;…but with no neighbour, and whole in himself, he is Thou and fills the heavens. This does not mean that nothing exists except himself. But all else lives in his light.”

Both utilitarian relationships of power and reciprocal relationships of love can contribute to longevity.  There is a longevity bonus attached to social status and power, and a separate correlation with family, sexual contact, and loving connection.



The protective effects of marriage have been known a long time.  Darwin quoted William Farr’s study of the French (1858), finding that marriage (except teen marriage) is associated with better health and lower mortality.  But marriage is difficult to disentangle from economics, access to health care, social standing and a host of other correlates. This paper finds that after correcting for everything under the sun, married men have 7% lower mortality, and women 4% lower, compared to unmarried.  It’s the human connection that counts.  “Although marriage keeps people alive, it does not appear to work through a reduction of stress levels.”  Two kinds of stress must be distinguished.  The stress of poverty or low social station or suffering abuse and contempt of another human is bad for your health and longevity.  But caring for others, taking on responsibility, leading an active, empowered and demanding life can be beneficial [ref].

Both women and men are at highly elevated risk for death during the months immediately following the death of a spouse [ref].


Social correlates of telomere length

It takes a long time to measure the effect of anything on human mortality.  Elissa Epel has pioneered the use of telomere length and telomerase activity as proxies for life expectancy.  She has found telomere loss to be associated with the bad kind of stress—feeling trapped by circumstance, powerless, stuck living in a way that is not what one wants.  Worry shortens your telomeres.  She found telomere connections to a variety of healthy living habits, including exercise, weight loss and meditation.  Suppression of telomerase can be detected from a single experience of humiliation that is tame enough to pass muster with an ethical review board.  This study finds that depression, anxiety and trauma leave their mark on telomere length in men but not women.  Young women also survive adolescence with more of their telomeres intact than young men.  Do men somatize their stress more than women?

Epel and her mentor, Liz Blackburn, have been slow to acknowledge the (now overwhelming) evidence that telomere shortening has a causal relationship to mortality.  They write of telomere length as a “marker” that tells a tale about past stresses and traumas.  They look for a proximate cause in inflammation and oxidative stress, but stop short of asking for a deeper, evolutionary significance.



There have been many studies seeking to connect fertility to longevity in women.  The consensus is a small positive connection—women who have more children tend to live slightly longer.  A message that stands out from this: for women, giving birth after age 40 offers a big bump in longevity, equivalent to setting your aging clock back more than 3 years.  For fathers who have children late in life, the data is thinner, but what data I could find indicate a benefit almost as strong.  The most relevant study I could find was for an Amish population, “a population characterized by large family sizes and close-knit familial units.”  Seven children was average  for these families.  Longevity of both mothers and fathers increased with each additional offspring, up to the 14th child.  But not beyond.

Less clear than the statistics is the interpretation. In my mind, this is all about caring.  When we stay involved in our children’s lives and care about them, there is a benefit for our health, mediated through neurochemistry.  Just my opinion.

(One prominent study finds a negative association between female fertility and longevity, and I have re-analyzed their data to show a positive effect.  The study was co-authored by Tom Kirkwood, best known for the theory that the reason for aging is that the body needs to spend energy on reproduction.  You gotta wonder when the one study that marches to the beat of a different drummer is done by the person whose reputation depends on the contrarian result.)



How could Mother Nature be so politically incorrect?  It is a sad and stubborn fact that, independent of all else, money is a strong predictor of longevity.

In 1980, the poorest one tenth of Americans lived 3 years less than the richest tenth.  By 2000, that gap had widened to 5 years [ref].  It is wider yet today—possibly as much as 14 years for males, 8 for females if this study is to be believed.

You would think there isn’t much difference in access to medicine within the top 1% of family income, but even there, the rich end of the top 1% lives half a year longer than the slightly-less-rich end [ref].

This is a psycho-social effect, connected to prestige and status.  It has little to do with access to health care.  We know this because the wealthy people in poor countries are living longer than the middle classes in wealthy countries, who have comparable incomes and perhaps better access to medical care.



Redeeming Mother Nature’s rep is this study of the Flemish Renaissance which tells us that elite musicians and poets, though poor, lived as long as wealthy non-artists.  Maybe orchestra conductors have just the right combination of leadership and aesthetics to maximize longevity.



A classic study [1943] by an Ohio Medical professor compared lifespans of historical figures in many different fields.  Musicians do better than painters.  Leaders in democracies do better than hereditary monarchs.  Philosophers live longer than poets.  The main conclusion that Lehman puts forward is that late-bloomers live longer than child prodigies**.  This has convinced me that Hillary, Bernie and The Donald don’t really want to be President—they’re in the race for a longevity dividend.




Frequency of sex is a positive predictor of longevity.  The best-known study came from Caerphilly in South Wales [1997].  Men 45-60 who were sexually active had half the mortality rate of men who had sex less frequently.  (I’ve been unable to find corresponding data for women, or more recent data for men.)  The effect seems to be more psychosocial than physiological, because the association is stronger with frequency of intercourse than with masturbation frequency.  (The article in British Medical Journal is written with a British sense of humor, and the authors make a point of debunking folk wisdom and the many religious traditions that associate orgasm with a depletion of vitality, and are especially tough on onanism.)

I think it’s not an accident that the hormone oxytocin is associated with youthful metabolism and is produced in response to intimacy and feelings of closeness.  Oxytocin spikes in an orgasm.



In this study, a crude measure of happiness was associated with a 20% drop in all-cause mortality.  From everything else we’ve seen, this would seem to be unexpectedly low.  If happiness could be more reliably measured and separated from other variables, it might loom even larger.  “For a 70-year-old man of average health, satisfaction of one standard deviation above average promises a 20 months longer life.” [1989]


The Bottom Line

Tilting the odds for a long life is not just a matter of discipline and abstemious living.  A lot of the things you can do to live a long time are things you want to do, or things that will make your life better right now.  Turn off your computer and spend time with a friend.


* “Only connect” is a refrain from E.M. Forster’s novel, Howard’s End
** Lehman emphasizes that much (but not all) of this is a selection effect: If you attained greatness at age 50, that means that you didn’t die before you were 50.

Social Correlates of Longevity—Part I

Starve yourself.  Exercise until it hurts.  Buy expensive supplements and stay away from the foods you love most.  You may have the impression that living a long time is no fun at all.

But the good news is that the most powerful life extension strategies are things we want to do anyway.  Live in a way that makes you happy.  Connect deeply to friends and lovers.  Spend time with your children.  Enjoy sex more frequently.  Take leadership in your community.  Express yourself artistically.

The very reason that aging evolved is to stabilize death rates for the sake of the community.  How can we be surprised to learn that the biggest factors affecting our life expectancy are not individual life style but social and communal connections?



Human genetics were shaped in a history of competing small tribes.  What I have long wondered about is that a well-functioning tribe needs a lot of loyal followers and one resolute and charismatic leader.

All animals living in a body, which defend themselves or attack their enemies in concert, must indeed be in some degree faithful to one another; and those that follow a leader must be in some degree obedient.
— Darwin, The Descent of Man

Somehow the leaders and followers had to come from the same gene pool.  Selection is simultaneously for strong-willed leaders and compliant followers.  And when we look today at the variety of personalities, we may observe the successful results: most people are indeed content to take their views and opinions from the community around them, to perform faithfully the task allotted to them, to raise few questions.  And yet there are plenty of us—all of my readers, I’m sure—who question authority, think independently, and who are in the habit of pro-active assertion.

How nature has arranged this, I can only imagine.  My guess is that there are infrequent combinations of genes that lead to independent-mindedness.  But there must also be a great deal of phenotypic plasticity.  That’s a five-dollar word describing a phenomenon biologists don’t understand very well.  Each individual is born with the potential to develop in a number of different directions, and adapts epigenetically within a single lifetime to choose one destiny among many.  Somehow, animals and people figure out when leadership is demanded of them, and respond accordingly, and they shut up and obey orders when appropriate, which for most people is most of the time.

The relevance of this to aging is that changes of leadership are disruptive and costly.  Many a tribe must have fallen victim to neighboring tribes during times when old leadership has died or succumbed to senility, while new leadership is distracted by jostling for power.  A beloved leader with a loyal following was and is a great asset to the community.  It would have served the community well if evolution might have arranged for leaders to have a longer life span than followers from the same community, the same pool of genes.

The take-home message:  Cooperative leadership is good for your health.  Earn the love and respect of your neighbors for your contributions to community life.


Glass half empty / Glass half full

Depression is a big risk factor for every disease that has ever been studied, and depression takes years off a person’s life.  The effect is hard to quantify because people who suffer from depression are more likely to have addictive dependencies, less likely to have healthy diets, less likely to exercise, less likely to have supportive social relationships.  The indirect toll of depression makes it hard to measure the direct effect independently.

This study of telomere length in heart patients found that depression accounts for 2½ years of excess telomere attrition.

I think of depression as one side of a continuum, from a full capacity for awareness and open-hearted enjoyment at one end of the spectrum to loss of all vitality and incapacitating numbness at the other end.  But the culture of Western medicine has led to a perspective from which depression is treated as a chemical imbalance in the brain that can be objectively diagnosed, present or absent with no “in between”.

In my view, this accounts for the fact that when psychologists study the health effects of a positive or negative outlook on life, they treat depression as an artifact that warrants separate treatment in their statistics, lest it bias their results.  It is the more remarkable, then, that even after removing from their sample men who are clinically depressed, the authors of this study still find that dispositional temperament accounts for 9 years of life expectancy.  Among a thousand men aged 64-84, those who leanded toward pessimism had more than twice the cardiovascular mortality rates of those who were disposed toward optimism.

9 years of added life is an effect that stands out head and shoulders among the effects that epidemiologists are wont to study.  Points of comparison: If cancer were completely eliminated, it would add 4 years to life expectancy.   Estimates vary for years lost to obesity in America, with a range of 3 to 8 years. Smoking is associated with 10 years of lost life, before subtracting a correction for indirect risk factors that correlate with smoking.


A speculation concerning depression and evolution

Why is depression such a common malady in our culture?  If depression is so bad for us, why has evolution put up with it?  My conjecture is that this is related to the need for phenotypic plasticity in the choice to become leaders or followers.  The genes for leadership must be preserved in the community, and yet most people with genes for leadership must be convinced, nevertheless, to live their lives as loyal followers—else the community would be rent by dysfunctional power struggles.  Depression is nature’s way of keeping too many people with leadership genes from disrupting the authoritarian structures of their community.


Social status

Frequently cited in this regard is a fertile long-term study of health and class in the British civil service system.  The Whitehall Study began in 1967 and continues to this day.

Nearly half a million Brits participate in Her Majesty’s Service, and there are more than 20 grades and subgrades, in a clearly-defined hierarchy of who gives orders and who takes them.  There is a close analogy to grades of military officers.

High-level officers are generally better paid and can afford a more comfortable life.  But medical care in Great Britain is socialized, and disparities in standards of care are relatively small.  There are also differences in family wealth that make the social service grade an independent measure of status, and not merely a surrogate for wealth.

The remarkable finding is that each grade of the service lives longer on average than all the grades underneath it.  Social status is tightly correlated with longevity.




A college education is worth ten years of life to a black male, but only 3 years to a hispanic female.  I don’t think it’s what they learn in school that makes the difference, but the career opportunities and the social connections that come with a college degree that account for the statistics.  I would guess also that there is a good deal of filtering in the process: preferential selection of people with patience and discipline who are inclined  to think about their future. This study attempts to separate the effect of education from filtering for iwhat the author calls “conscientiousness”.  He concludes that both play a role in extending lifespan.  And here is a more recent, drier and more thorough account of differences in life span by race and education, focusing on completion of high school.  A high school diploma seems to be be associated with 5 extra years for a white male, but almost nothing for a black female.


The Bottom Line

To live in a way that is engaged and self-actualized is the best thing you can do for your longevity.  Strong family ties, love, sex, power and money are all good for your longevity.  (Some of these items aren’t in todays blog, but they will be in Part II next week.)


END of Part I

CRISPR update

I believe that all we have to do to make ourselves younger is to turn on the genes that were expressed when we were young, and turn off the genes that are expressed when we are old. This will require both knowledge and technique; (1) knowing which genes these are, and (2) having a targeted mechanism for turning specific genes on and off in vivo. At this time, our technique is advancing nicely, outpacing the knowledge, thanks to CRISPR / Cas9.

I wrote nearly two years ago that CRISPR was a third-generation technology for editing the genome, which could also be adapted to “edit the epigenome” by turning genes off.  Turning genes on was, and still is more difficult.  The work-around is to add extra copies of the gene, which can be a higher-risk operation, because the body has no evolved mechanisms for deciding when to turn the extra copy on and off.

The older technology of AAV (Adeno-Associated Virus) can be deployed within the living body, transfecting large numbers of cells and inserting a payload gene (of limited size); but there is no control over where in the genome the gene is inserted, and so there is no assurance that it is turned on or off at appropriate times and places.  The newer technology of CRISPR is precisely targeted, can remove or insert a gene, can turn a gene off (but not on).  But so far it is only possible in cell cultures in the lab, and not for large numbers of cells within a living organism.

There are thousands of clinical trials worldwide for AAV gene therapies, and last week the first clinical trial was announced for CRISPR as a cancer therapy.  The protocol is to extract the patient’s own T cells from a blood sample, then modify the cells in lab culture using CRISPR.

The researchers will remove T cells from 18 patients with several types of cancers and perform three CRISPR edits on them. One edit will insert a gene for a protein engineered to detect cancer cells and instruct the T cells to target them, and a second edit removes a natural T-cell protein that could interfere with this process. The third is defensive: it will remove the gene for a protein that identifies the T cells as immune cells and prevent the cancer cells from disabling them. The researchers will then infuse the edited cells back into the patient.

This is a modest first effort in many ways–not just that it is limited to 18 patients and nominally seeks only safety data.  There is great potential for sensitizing the T cells to the patient’s particular cancer.  It would also be logical to combine CRISPR with stem cell therapy.  A patient’s bone marrow stem cells could be harvested, modified with CRISPR, and re-injected, whereupon they would create an ongoing supply of sensitized T cells.  Neither of these ideas will be attempted in this first trial.

The Nature article goes on to recall the tragedy of the first gene therapy trial to kill an 18-year-old patient in 1999, and how gene therapy research lost a decade dealing with safety issues after that.

Hydrodynamic Gene Therapy

This is a kind of brute force method for delivering a genetic payload.  A large volume of dissolved DNA is injected directly into a vein, rapidly enough to raise blood pressure system-wide for a few seconds.  The pressure pushes some of the payload through capillary walls.  This system has been widely adapted for rodent experiments, with a tail vein used as the delivery point.  It has even been tried in humans.  But it is crude and untargeted.  Penetration rates remain low, and collateral damage is unavoidable.


Incorporating CRISPR into Gene Therapy

Of course, what we would really like is the specificity of CRISPR combined with the wide in vitro delivery provided by AAV gene therapy.  The complete machinery for Cas9 to break the DNA strand in a chosen location is too large a payload to fit within the AAV virus.  So marrying CRISPR to AAV has been the subject of some ingenious research just in the last two years.  The first successful experiment was announced this past winter in Nature Biotech.  An MIT-based research team reports that in a single treatment, they are able to make targeted modifications to 6% of white blood cells in a lab mouse.  I’m out of my depth reading about their technique, but from what I understand, there are separate delivery systems for the gene (via AAV virus) and for the targeting (via nano-particles of Cas9 enzyme dissolved in organic fats).  The former makes its way efficiently to the cell nucleus, because that it is what the virus was evolved to do.  The latter must be relied upon to diffuse into the nucleus at random, and the microencapsulation facilitates its transit.

Once inside the nucleus, the Cas9 breaks the chromosome in just the right place, and the virus seizes the opportunity to insert its payload conveniently.  The authors emphasize the importance of eliminating the Cas9 promptly.  If it were part incorporated in the virus, there would be a danger of ongoing, long-term DNA breaks; but the nano-particles containing Cas9 are short-lived.

Here is a recent review of progress in combining CRISPR with viral vectors for gene therapy, written at a technical level.  The Concluding Remarks section speculates on the possibility of combining three separate viruses for delivery of the CRISPR template, the Cas9 enzyme, and the genetic payload.  The obvious problem with such a system is going to be that each of these three viruses has a limited penetration, and it will only be in cells that all three viruses have transfected that the right thing happens (double-stranded break in just the right place, followed by insertion of the payload gene).  In the much larger number of cells that receive one or two of the viruses, there is the probability of damaging side-effects.


A Tangle of Signals

In the fable of the Sorcerer’s Apprentice (and a hundred myths from ancient Africa, Europe and the Orient), the protagonist is attracted to the quick acquisition of power, less interested in the slow acquisition of wisdom.  Exercise of power without wisdom is the classical gateway to tragedy.

And so we see our labs acquiring control over the genome and over gene expresssion proceeding apace, while understanding of the tangle of signaling pathways lags behind.  Many of us are now convinced that aging is controlled by epigenetic signals.  We are beginning to map difference in gene experesssion that occur with age.  But which genes are upstream and which are downstream?  Which are cause and which are effects?  Which are tissue-specific, and which are systemic signal molecules?

It now appears that the technology to modify gene expression will be ours before we know how to use it.