A Link Between Mechanisms of Calorie Restriction and Ketogenesis

Calorie restriction slows aging in most species and lineages tested to date, though the size of the effect on life span diminishes as species life span increases. Calorie restriction produces very similar short-term health benefits in humans and mice, but mice live as much as 40% longer as a result. We certainly do not. The necessary human studies have yet to run, but the consensus in the research community is that five years of additional life expectancy for calorie restricted humans is about as much as could be expected. The beneficial response to calorie restriction isn't just one mechanism under the hood, though increased autophagy appears to be an outsized contribution. Calorie restriction changes just about everything there is to be measured in cellular metabolism, shifting the behavior of many networks of linked genes and protein interactions. Given these networks, there are a range of other means of provoking some of the same effects. This is true for most aspects of cellular biochemistry: there is never only one way to produce change.

Among the alternative means to touch on some of the changes involved in calorie restriction are intermittent fasting without calorie deficit, protein restriction, such as low methionine diets, and carbohydrate restriction - the much-hyped ketogenic diet, which is the topic for today. All structured popular diets are much-hyped, of course, surrounded by a moat of nonsense and borderline fraudulent commerce. It has to be said that if people spent one hundredth of the effort they put into considerations of diet into useful medical research, we'd be a lot closer to solving the problem of degenerative aging and age-related disease. So much light and noise for so little gain. No alteration you can make to your eating habits will reliably let you live to see a century of life, and even those people with the best, most optimal diets are still decrepit and much harmed by age in later life. The degree of difference that can be made just isn't large enough to justify the investment.

I point out this sort of research because it is interesting, not because it is the road to large increases in healthy human longevity. Researchers are progressively uncovering the details of shared mechanisms touched upon by a wide variety of dietary interventions, exercise, and other environmental factors known to influence health. Under the hood just a few core clusters of cellular behaviors are responsible for steering the bulk of natural variations in the pace of aging within a given species. These natural variations in aging and in health are tools that can be used to learn more about the intricacies of mammalian biochemistry. That is the primary output of these research efforts: knowledge, not practical therapies. You, I, and anyone else can set forth today to obtain all of the potential benefits under examination here: just choose to exercise regularly and eat less, and while doing it give some thought to the myriad fascinating biochemical changes taking place throughout the body and brain. I think we all understand the scope of what is possible via these methods, and just how limited they are in comparison to the potential of the nascent industry of rejuvenation therapies, treatments such as senolytics that are based on damage repair rather than tinkering with the recreation of calorie restricted metabolic states.

Ketogenic diet improves healthspan and memory in aging mice

Eating a ketogenic diet - which is high fat, low protein, and low carbohydrates - ramps up the production of the ketone body beta-hydroxybutyrate acid (BHB). While small studies in humans with cognitive impairment have suggested that BHB could improve memory, this is the first study in aging mammals which details the positive effects of BHB on memory and lifespan. "We're looking for drug targets. The ultimate goal is to find a way for humans to benefit from BHBs without having to go on a restrictive diet."

Reserchers carefully designed three diets that were matched in every way except fat and carbohydrate content: a normal high-carbohydrate diet, a zero-carbohydrate ketogenic diet, and a high-fat, low-carbohydrate diet that was not ketogenic. Mice were fed the ketogenic diet intermittently to prevent them from becoming obese, starting at one year old - middle age for mice. The ketogenic diet-fed mice had a lower risk of dying as they aged from one to two years old, although their maximum lifespan was unchanged. Another group of mice underwent memory testing at both middle age (one year old) and old age (two years old). Mice that had been eating a ketogenic diet performed at least as well on memory tests at old age as they did at middle age, while mice eating the normal diet showed an expected age-associated decline. Mice who ate the ketogenic diet also explored more, and their improved memory was confirmed with another test a few months later.

"We were careful to have all of the mice eating a normal diet during the actual memory testing which suggests the effects of the ketogenic diet were lasting. Something changed in the brains of these mice to make them more resilient to the effects of age. Determining what this is, is the next step in the work. Looking at gene expression, the ketogenic diet suppressed the longevity-related TOR pathway and insulin signaling and up-regulated the fasting-related transcription factor PPAR-alpha, a master regulator that helps the body more efficiently metabolize fat. Exercise also creates ketone bodies - that may be one of the mechanisms why it shows such protective effects on brain function and on healthspan and lifespan."

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

BHB is a normal human metabolite that is synthesized in the liver from fat, and then circulates throughout the body as a glucose-sparing energy source. It is intrinsically produced during states such as intermittent fasting and dietary restriction (DR) that result in extended longevity, cognitive protection, cancer reduction, and immune rejuvenation. Recent work has elucidated an array of signaling functions of BHB that suggest that BHB might itself regulate inflammation and gene expression, with implications for health and longevity.

A ketogenic diet is one means to deliver high levels of BHB for a prolonged time outside of a fasting or exercise context. Ketogenic diets generally contain little or no carbohydrate and stimulate endogenous ketogenesis. We sought to test whether a ketogenic diet carefully matched to comparison diets could enhance the longevity and healthspan of normal mice, and to elucidate potential molecular mechanisms of such effects.

We show that long-term exposure to a ketogenic diet, fed every other week starting in middle age, reduces midlife mortality and preserves memory in aging C57BL/6 male mice. Similar feeding of a high-fat, low-carbohydrate non-ketogenic diet appeared to have an intermediate effect on mortality, but survival of this group could not be definitely distinguished from either the control or ketogenic diet groups. These results might be interpreted in the broader context of the health effects of DR and of segmental DR mimetics such as metformin and rapamycin, and suggest that one or more aspects of a ketogenic diet may similarly act as a segmental DR mimetic.

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