Caloric restriction is the gold standard life extension strategy, validated over thousands of experiments in many animal species. How can we reconcile this with consistent findings that people who are slightly overweight live longer than normal or underweight folks?
The one fact that everyone in the field of aging agrees on is that animals fed less live longer. This is the result that got me interested in the field 25 years ago, and it is still the most robust finding in the field, verified in dozens of species from yeast cells to Rhesus monkeys.
Are humans different from all other animals?
Last month, a study came out of Ohio State U based on the famous Framingham database, including medical and demographic information on 5,000 people and their offspring, tracked over 74 years. The take-home message was that the people who lived longest were average weight when young and gained weight during their middle years. There were not enough people who had actually lost weight to constitute a subgroup, but the group identified as “low-normal weight” all through their lives showed up with 40% higher all-cause mortality than those that gained weight.
I wrote about this subject in my book, and in one of my first posts on ScienceBlog, back in 2012. The post was titled Ideal Weight may be an Illusion, and I concluded that
“For any given individual, it’s probably true that
the less you eat the longer you live.”
The argument went thus: Weight is mostly fixed by genetics, and the genetic component of weight does not affect longevity. It is relative calorie intake that affects longevity, relative to genetics, body type, and metabolism. For example, a study of genetically obese mice found that they had shortened lifespans if they were fed ad libitem, however, if the obese mice were calorically restricted, they actually lived longer than genetically normal mice, and even longer than CR normal mice, despite the fact that they still appeared plump.
This line of reasoning led me to hypothesize that the reason overweight people tend to live longer is that they are motivated to restrict calories, whereas people (like me) who don’t get fat no matter how much we eat feel no social pressure to restrain our gluttony.
I thought at the time that we ought to see this effect much more in women than in men, because overweight women are ostracized in our culture, whereas men are not. What I found, contrary to my prediction, was that the BMI with lowest mortality (in Japan) is 23-25 for men, compared to 21-23 for women [Matsuo, 2012].
So, is it time to consider the possibility that caloric restriction doesn’t extend human life expectancy?
New Ohio State Study
The new study is based on the 74-year-old Framingham cohort, people whose health and daily habits have been followed over time. Also followed was a Framingham Offspring cohort, the children of the original Framingham cohort. Almost all the original cohort have now died (so we have extensive mortality data), but many of the offspring cohort is still alive. The authors treat the two cohorts separately, and get somewhat different results for the two cohorts. Dr Zheng was kind enough to send me the full preprint with supplemental tables, and since it’s not yet available online, I’ve made it available for you to read here on GDrive.
The study looks not just at BMI but also at the change in BMI over mid- to late-life years. They classify the trajectories in seven groups, and analyze them using a Cox model. They find that the group that has lowest mortality had an average trajectory beginning at BMI=22 at age 30, increasing gradually to BMI=27 at age 80. The group was broadly defined, so that initial BMI could be anywhere from 18.5 at the low end to 25 at the high end.
|Cox Proportional Hazard Model
This statistical method is standard for studies like this evaluating effect on mortality. It is designed to take into account the steep rise in mortality with age, and weight different deaths according to when they occur. The standard assumption is that the mortality curve with age is changed by a multiplicative factor associated with each variable. The mortality curve retains the same shape across ages, but it slides up or down (on a log scale) according to which factors apply to a given subgroup. For example, having a graduate degree may multiply your risk of dying by 0.9 across the board, and eating red meat may multiply your risk by 1.2, so the model actually derives these numbers by assuming that meat-eaters with a graduate degree will have a relative probability of death 1.08 times the control group, and this applies at every age. (where 1.08 = 0.9 * 1.2)Is this quantitatively realistic? Everyone knows it is not, but it yields a single number which is a good benchmark for different longevity factors, and it allows different studies to report their results in a common format for comparison.
Division of subjects into seven groups was somewhat arbitrary, and was done to facilitate statistical analysis. The red railroad tracks represents midline of the trajectory associated with “longest lifespan”, defined above as the minimum Cox factor. The lowest weight group was associated with a Cox factor of 1.4, meaning 40% more likely to die (at a given age) than the red railroad track trajectory.
On the other side
CR extends lifespan in almost every animal model in which it has been tried. I won’t dwell on this, because it’s so well known, but I’ll note that CR works better in short-lived animals, as a percentage of lifespan and the enthusiastic projections of Roy Walford now seem overstated. I have said that I think CR in humans is good for 3 to 5 years. Do I still think so? There is good evidence for CR in humans.
- Food shortages during World War II in some European countries were associated with a sharp decrease in coronary heart disease mortality, which increased again after the war ended.[Fontana, 2007]
- Fontana performed in-depth metabolic profiles of people identified from the Caloric Restriction Society who were disciplining themselves to eat less. Relative to people at a comparable age, he found “a very low level of inflammation as evidenced by low circulating levels of C-reactive protein and TNFα, serum triiodothyronine levels at the low end of the normal range, and a more elastic ‘younger’ left ventricle, as evaluated by echo-doppler measures of LV stiffness.” 
- There is at least preliminary evidence that weight loss tends to set back the aging clock, as measured by several methylation algorithms 
- Higher BMI is associated with older methylation age 
- C-reactive protein in the blood, the most common measure of inflammation, increases with increasing BMI 
- Loss of insulin sensitivity is a hallmark of aging, driving many age-related diseases. There is a strong correlation between BMI and diabetes 
- BMI is linked to most common cancers, the #2 source of mortality. Here’s a good review by Wolin .
- BMI is also a factor in cardiovascular disease, the #1 killer. This study from Malaysia  found a trend of increasing CVD at every BMI level, but — like other studies — also found that all-cause mortality was lowest for BMI 25-30, which has traditionally been called “overweight”.
So, why doesn’t weight gain show up as a risk factor for faster aging?
I will continue this discussion in Part 2, and try to resolve this paradox in part, but (spoiler alert) I remain puzzled, after a month of reading on the subject.
So we can now add ‘long-lived’ to ‘fat and happy’? 😉
Well. Happiness is a factor often attributed to those living a longer life.
Higher BMI probably also means higher muscle mass which is associated with longevity. Although when digging in it looks like muscle strength is more important than muscle mass although they are normally pretty closely linked.
Maybe CR lab experiments don’t reflect real world disease risk and humans need the “reserve” that a higher BMI gives.
telomeres and rapamycin
Inter mixed cohorts may be at play, though effect size may be hard to determine. For example, low BMI may not be able to differentiate between people who are chronically or terminally sick and healthy slender.
Also people who tend not to increase BMI despite most people generally losing muscle mass with increasing age, may have factors that protect them from weight effects of over eating. I suspect some perhaps many people with such a benefit to their weight might get a tendency to overeat.
If that hypothesis is true, overeating may be detrimental to some extent even without gaining weight.
“They find that the group that has lowest mortality had an average trajectory beginning at BMI=22 at age 30, increasing gradually to BMI=27 at age 80.”
There have been a LOT of poor quality studies on BMI and mortality, the highest quality studies are the ones that have the longest follow up periods, and these seem to conclude that BMI 20-22 is ideal for longevity, see:
As for BMI in the elderly though, I’m very interested in this topic, since frailty is one issue, muscle loss another, and having fat reserves to protect one’s vitality when sick yet another possible factor. I’m also wondering if how they calculate BMI in the elderly is flawed? BMI is based on height, but on average we shrink about a quarter to a third of an inch per decade for every decade after age 40. This causes BMI to rise even without weight gain. Maybe researchers should be using MAX lifetime height for the formula instead of current height?
Another probably important factor in all of this is brown fat.
It explains why “constitutionally lean” people are healthier and live longer, it explains the improved insulin sensitivity, it explains the hormone profiles of super centenarians, it even explains why women generally live longer than men! See: https://www.longecity.org/forum/topic/87615-brownbeige-adipose-tissue-activation-bat-via-cold-exposure-and-diet-for-health-and-longevity/
If you are 5’10” and have 32 inch waist and 40″ hips and weigh 190 pounds, you might be a professional athlete; but if you have 40 inch waist and 32 in hips, you are in very bad shape.
BMI lumps muscle which is good and visceral fat which is bad. Result is worthless measurement.
Very good to point that out
Perhaps, it is not how much a person eats, but what they eat.
For example a person can gain weight eating a lot of bulky, fiber rich, low starch whole vegetables and grains that add fiber along with low fat meats and fish, and very little sugary foods.
That type of diet, wont adversely effect cholesterol or triglycerides, even if a person is plump, if that person that is not genetically prone to have high cholesterol or triglycerides.
Also as mentioned perhaps people who can eat as much as they like and do not pack on the pounds, eat more of the wrong type of foods.
For example, and this is anecdotal of course…….I had a friend who never gained weight. He would boast that he could, and did, eat whatever he wanted. He also boasted of drinking heavy cream almost daily, and never put on a pound.
He died in his 60s of heart disease. He was always slim and very active, still…..
Of course, it is possible he was simply genetically prone to heart disease.
I think the Linus Pauling ideas on heart disease have merit. It is likely that without somewhat higher vitamin C intake, too much saturated fat in the diet could inevitably lead to heart disease.
Thank you for your amazing work. I am attaching a link to Keith Devlin’s (a mathematician) about the origin and purpose for the BMI.
(apologies for not being able to create a hyperlink)
It seems having a good starting point with a reliable measurement which could translate down to the individual might be a good step in the right direction.
Thank you again!
Very low BMI are often associated with very low muscle strength causing low bed, worse energy metabolism and increased injury and accidents. However, with effort and consistency muscle strength and mass can be maintained during moderate CR and IF. I bet if you could test the few subjects motivated to achieve this, you would find greatly increased health and longevity.
BMD = bone mineral density
Yes I’ve not researched it but there was a news article that pointed that someone with very high CR experienced significant bone loss to the point he had significant problems with his spine.
I’m not sure if more moderate levels of CR might have some degree of bone loss in longer lived animals. But the primate studies hint that at least moderate levels might not have such issues.
In any case there are a few substances believed to increase bone mineral density, such as resveratrol. Which might help avoid the problem.
I would say the answer to this conundrum Josh, is Insulin Sensitivity. Those that stay very thin are highly insulin sensitive. Any slip up and all that glucose gets sucked into cells causing aging, particularly in the most insulin sensitive tissues like the liver. But put on a little weight and insulin resistance rises. In a way this is a defence against aging.
Of course this is not a recommendation to become obese.
Efficient utilization of glucose with minimal insulin by muscles and brain is good. High circulating blood sugar and insulin due to insulin resistance is not.
If that were true then rapamycin would not extend life.
The fact of the matter is that the harm from higher circulating glucose is far smaller than the aging caused by cells metabolising it.
I recall reading that the body repairs itself during hunger, not during nutrition. Perhaps the percentage of time spent hungry is the important factor
This is a good point, at some level. Intermittent hunger/calorie restriction windows may be more beneficial than chronic, day-to-day calorie restriction to extend life in humans.
Valter Longo of USC, who wrote “The Longevity Diet”, advocates for a five-day fasting mimicking diet, as well as 72-hour water fasts, but he does not advocate Time-Restricted Eating of more or less than 12 hours each day:
“It turns out that it is important is to stick very close to 12 hours of feeding and 12 hours of fasting. If you eat 15 hours a day or more, that starts to be associated with metabolic problems, sleep disorders, etc. This is a new habit. If you ask centenarians, it is almost unheard of in these groups. But also, if you fast for longer than 12 or 13 hours, that starts to be associated with problems like gallstone formation, and we also know that longer fasts can lead people to skip breakfast. There are a number of studies, and we have our own data supporting this, showing that skipping breakfast is associated with increased risk for overall mortality and cardiovascular disease. So not only is it not good, it is bad for you.”
Additionally, Longo has data on healthy impacts of 72-hour fasts:
“… research by Valter Longo of the USC Leonard Davis School on how fasting for three days can improve a person’s health. The six-month study was done on subjects going through chemotherapy. “When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged,” Longo said.”
With all that said, I like to remind myself that the point of all this is to understand the longevity activating mechanisms that are triggered (eg. autophagy, mitophagy, senescent cell clearing, etc) in a calorie restricted state (such as time-restricted/intermittent fasting, diet mimicking fasting, multiple-day fasts, etc). It’s much easier doing tests on humans in smaller time frames, and comparing to the studies of chronic CR in other species. At that point, we can figure out how best to apply to our lives — whether in supplements/drugs or IV/blood treatments that activate the same longevity mechanisms, or by actually doing a 3-day fast on a monthly basis.
Eric, I respect Valter Longo’s research, but I disagree on his view regarding IF. There are numerous studies showing health benefits from IF:
There is a general consensus within the anti-aging field, that some sort of intermittent fasting (not just overnight fasting) has numerous health and longevity benefits. I’ll keep skipping breakfast, until I see some more convincing data.
My personal observation: after being on IF for 7 months (6pm till next day’s noon) my waist increased 1 inch while the weight dropped. Since reading that article (3/4/21) I am off 18 hour IF and keep it at 12. The weight is stable and the waist is slowly shrinking.
I did 18hr IF for years and the benefits were minimal at best.
I think it is highly individual. I feel mentally sharper and more focused, when I am in the fasted mode. In order to really boost autophagy, DNA repair, immune rejuvenation etc, prolonged fasts for 3-4 days are needed.
This subject comes up over and over again. I think people are reading too much into the epidemiological studies and forgetting that association does not mean cause and effect. There is a huge difference between being an outlier with unusually low BMI merely because of genes and being an outlier because of eating little and taking care of ones health. The latter would be healthier than the former but the epidemiological studies don’t differentiate between the two.
Also BMI is a poor measure of health (because it does not differentiate between muscle mass and fat mass). While the evidence on the benefits of calorie restriction suggests that it is very beneficial for longevity people must not forget that aging tends to result in a loss of lean body mass and frailty and lack of appetite which then results in a lower BMI. I think low BMI at oldest ages is therefore more a result of aging poorly rather than a cause of it.
My pet theory is that some of the aging benefits of CR seen in model organisms can be attributed to the inherent necessity of time restricting these organisms’ feeding in order to limit calories. I’ve seen many mouse studies which did not control for the circadian effects of ad libitum feeding versus scheduled feedings. For example; see the Weindruch et al (1986) paper linked in the cited De Gray review. As calorically restricted humans are not necessarily eating on a more consistent schedule than their normal-intake counterparts (perhaps the opposite), we would not expect to see the benefits of well synchronized circadian rhythms on their mortality. This could also explain some of the positive health outcomes observed during wartime rationing. A lot of the other mentioned positives of CR in humans could merely be benefits of not being metabolically unhealthy or too overweight.
This association of being in the overweight category and having protection from multiple chronic illnesses has been observed for a long time and is widely referred to as the obesity paradox. In 2015 Katherine Flagal raised quite a stir when she evaluated 97 studies on close to 3 million people and found significantly lower mortality rates in those with bmi’s of 25-30 range. This was published in JAMA:
I think that it’s safe to say that bmi is flawed since it fails to take into account muscle, age, sex, and bone structure. That being said, it does accurately predict body fat about 80% of the time.
The alternatives aren’t very good like underwater weighing ( difficult), MRI ( expensive), and even waist measurements ( not standardized).
We know without question that obesity is fraught with dangers and much of that is due to chronic inflammation. Is it possible that being mildly overweight is causing just enough inflammation to trigger a hormesis response and that is leading to the production of natural anti inflammatories like palmitoylethanolamide?
It’s certainly interesting.
I came across an Interesting Inflammation study:
“Development and Validation of Novel Dietary and Lifestyle Inflammation Scores”
The numbers from table-1 seem to explain why different diets etc.. work for thin, overweight and obese people to reduce inflammation.
The more extra weight you carry the more items with a high negative score you need to correct your inflammation.
The study includes various foods, exercise, smoking, overweight and obese, alcohol usage etc…
Positive scores reflect inflammation, negative scores reflect anti-inflammatory results.
The more negative the better. It appears you use a sum of the numbers to determine your score.
Josh Great article, I struggle with this conundrum as well on my longevity journey, I normally do 18 -6 intermittent fasting and also mainly Keto and paleo and sometimes I do 3-5 dry fasts, it reduces inflammation but I loose so much weight that people are worried about my health and say I look terrible, but when I up my calories 2 meals a day and train at the gym everyone thinks I look great but I know by my waist measurement is bigger so that’s increased inflammation. I just wonder sometimes do people have an innate ability to sense when you are healthy or is looking good and being healthy 2 different programs, looking good is growth so signaling to other people you are successful, but also tuning on your death genes as you are signaling to your body times are good and you better die off for the good of the group.