Will Calorie Restriction Extend Life in Humans?
Here is a commentary on what is known of the effects of calorie restriction in humans, and the prospects for determining whether or not it actually extends life in our species, from one of the foremost researchers in the field:
Calorie Restriction (CR) without malnutrition is the most powerful nutritional intervention that has consistently been shown to increase maximal and average lifespan in a variety of organisms, including yeasts, worms, flies, spiders, rotifers, fish and rodents. Far from merely stretching the life of an old, ill and weak animal, CR extends longevity by preventing chronic diseases, and by preserving metabolic and biological functions at more youthful-like state. In rodents, the CR-mediated preventive effects are widespread with major reductions in the occurrence and/or progression of cancer, nephropathy, cardiomyopathy, obesity, type 2 diabetes, neuro-degenerative disease, and several autoimmune diseases.Whether or not CR without malnutrition will extend lifespan in humans is not known yet, but accumulating data indicate that moderate CR with adequate nutrition has a powerful protective effect against the development of obesity, type 2 diabetes, inflammation, hypertension and cardiovascular disease, which are major causes of morbidity, disability and mortality. In humans calorie restriction without malnutrition also results in a consistent reduction in circulating levels of growth factors, anabolic hormones, adipokines and inflammatory cytokines, which are associated with an increased risk of some of the most common types of cancer.
Moreover, CR in these individuals resulted in an amelioration of two well-accepted markers of cardiovascular aging, i.e. left ventricular diastolic function and heart rate variability. These data indicate that CR exerts direct systemic effects that counter the expected age-associated changes in myocardial stiffness and autonomic function so that LV diastolic function and heart rate variability indexes in CR individuals are similar to those of individuals 20 years younger on a typical Western diet. Consistently, we recently found that CR without malnutrition results in dramatic changes of the human skeletal muscle transcriptional profile that resemble those of younger individuals.
More studies are needed to understand how macro- and micro-nutrients, endurance exercise, and other environmental and psychological factors interact with CR in modulating metabolic and molecular pathways that regulate health and longevity. Randomized, CR-controlled, long-term survival studies in humans will never be performed because of obvious problems with long-term compliance and costs of such a long study. Nonetheless, we hope that by following the health status of individuals practicing long-term CR without malnutrition, in particular of those who are now in their 70s and 80s, we could gain soon some information about the effects of CR on successful aging and healthy longevity in humans as well. Because we have detailed information about their close relatives' disease and survival histories, if we observe that as the [CR practitioners] age, they don't develop any of the metabolic abnormalities and/or chronic diseases typical of their parents/siblings, and live substantially longer than their relatives, this will be the best available proof that CR works in humans.
In 2006, I wrote and "published" (hiqnews.megafoundation.org/Does_CR_Delay_Human_Aging.htm) speculations concerning whether calorie restriction will extend human lifespans. I had just returned from the 4th annual Calorie Restriction Conference in Phoenix. At the conference, the buzz among the animal researchers... Steve Austed, Ed Masoro, Steve Spindler... was about the fiasco with the ongoing CR experiment at the National Institute on Aging. Both the control monkeys and the CR'd monkeys were throwing their food at their keepers and trying to bite them. The experiment had, (in their opinions) turned into a bit of a shambles. I thought to myself, "What are they going to do? I hope they're not going to try to put lipstick on this pig and try to palm this study off as a legitimate experiment. But what else can they do? A lot of time and money has been invested in this effort. If they say, 'Gee! Sorry, it didn't work.', they can kiss their careers goodbye."
At this conference, four gerontologists gave their (mutually exclusive) theories about why calorie restriction won't work in humans. The most prominent of them was Aubrey de Gray, who argued that CR effects evolved to allow animals to survive a year or two of drought or kindred hard times. The absolute life extensions that CR afforded were never more than a couple of years. It followed that CR in humans would confer no more than a couple of years of lifespan extension.
I thought to myself at the time that this had already beenovertaken by events in that Luigi Fontana and John Holloszy had already established (in 2004) that CR had rolled back the clock in 18 CR volunteers by 10 to 15 years.
In the two cases of unwitting lifelong CR with which I'm familiar... Luigi Carnero and Ralph Cornell... CR without optimal nutrition had, in my opinion, added 10 or more years to their lives.
I'm wondering if we'll someday learn that the NIH and University of Wisconsin primate CR studies failed (understandably) to take into account mental/emotional ("caged-up") factors that aren't as important to rodents and roundworms.
In the end, I guess "you plays your money and you takes your chance". Now, ten years after embarking on CR, I don't see any slippage in the 15-to-20 years of age reduction that calorie restriction afforded me back in 2003.
I think I should retract something I just wrote: namely, " The experiment had, (in their opinions) turned into a bit of a shambles." I have no right to quote them without their permission, and beyond that, those are my recollections from seven years ago. A better way to say it would be, "The experiment had, (in my opinion) turned into a bit of a shambles."
@Bob Seitz: In my opinion, one of the more interesting sidebars in aging research over the next decade will be how the research community reconciles the lack of evidence for life extension in humans as a result of CRON with the evidence for tremendous benefits in short term measures of health obtained through CRON. It's a puzzle. Ultimately an irrelevant puzzle when it comes to the future of longevity, as that will be determined by progress towards rejuvenation therapies such as the implementation of SENS, but still very intriguing.
So I look forward to an elucidation of the underlying mechanisms that enable humans and mice to have very similar short-term and mid-term responses to CR, and yet apparently quite different outcomes in life expectancy.
I like the way you've highlighted the riddle of the apparent discrepancy between short-term and medium-term benefits of CR in mice and men, versus the presumed lack of decadal CR life extension in humans. And, of course, CR would at best buy us a modicum of additional healthspan, versus the overriding SENS goal of untrammeled health and life extension.
In reading what I wrote, I'm troubled by, maybe, an implied criticism on my part of the NIA group who sheparded the NIA rhesus monkey CR trial. I certainly don't mean to criticize them. I know they did a thoroughly competent job, and published their results as the study required. I was recounting my private musings sitting in the conference sessions (as I remember them).
I'm suddenly realizing how easy it is to be impolitic on a public bulletin board like this(:-))
I can testify that a severe CRdiet (without malnutrition, which is a bit of a trick at 1200 calories per day) works. I have backslide due to the death of my parents, and I never want to feel like this again. Before and after numbers taken by my health insurer (for a discounted premium) back up my opinion.
CR plus telomere therapy such as TA65 are the best, so far at least, in my
humble opinion. Dr Seitz' 2006 paper was in inspiration for a 78 year old trying to
prevent degenerative disease.
Thank you. Dr Seitz, and now telomere restoration, for my continued health!!
Also use CR along with telomere reinforcement for healthy longevity
soon to be 87 years of age.