How Calorie Restriction Mimetics May Slow the Hands of Time
As many of you may know, I’m a big fan of calorie restriction. Done sensibly, with longevity as the goal, rather than weight loss, CR is a simple and effective way to support the function of many of the bodily processes that can help keep us younger longer, in the process, reducing the risk for many of the classic diseases of aging. But the idea of CR as a potential longevity-enhancer isn’t new -- it’s actually been around for over ninety years. As far back as the 1930s, scientists found that feeding lab animals less food — without starving them — consistently extended the length of their lifespans. From fruit flies, mice, monkeys to even a few Labrador retrievers, this pattern held up. Eat less, live longer. That simple – yet, for most of us, that hard.
This less-is-more CR approach became the earliest blueprint for what we now call longevity medicine. The animal studies demonstrated that cutting calories amps up metabolism – keeping blood sugar and insulin under control – and tames inflammation and triggers powerful cellular repair systems. That adds up to a lot of potential longevity benefits.
But here’s the tricky part: living in a constant state of just-a-bit-hungry isn’t fun or especially do-able for most of us. And by the time you hit your late 60s and early 70s, the weight pendulum tends to swing in the other direction. Weight, especially muscle tissue, gets tougher to hang onto and being too thin can actually increase the risk of frailty — even if your bloodwork rivals that of a much younger person.
But what if you could harness the benefits of calorie restriction without actually having to eat less? That’s where ‘calorie restriction mimetics’ (CRMs) come in, compounds that mimic the beneficial effects of CR. Here’s an introduction to this fascinating, and fast-evolving, anti-aging science, and a look at how CRMs may help you keep a spring in your step for as long as possible:
Why CR – and CRMs – matter.
Studies show that eating 30-50% less of an otherwise healthy diet helps many species live longer, get sick less often, handle stress better, and stay healthier as they age. Does it work for humans too? Studies show that CR produces these positive effects in rhesus monkeys, in evolutionary terms, our close cousins. Human trials are currently underway to find out for sure. But here's the thing - even if CR does work for us, who wants to drastically cut their food intake forever? That's why researchers are looking for "CR mimetics" - compounds that “trick” your body into responding as if you were eating less without actually requiring you to diet.
Get to know the CRMs.
So, what are CRMs anyway? Calorie restriction (CR) is straight-forward enough but it’s the ‘mimetics’ part that needs some explanation. In short, CRMs are the helpful nutrient compounds that mimic the biochemical and functional effects of caloric restriction, without requiring an actual reduction in calorie intake. The research has identified CRMs that target the same metabolic, hormonal, and physiological pathways that calorie restriction works through. They stimulate maintenance and repair processes, leading to CR-like effects on longevity and a reduction in age-related diseases.
Which compounds make the CRM cut?
A CRM worthy of the name should be able to reduce oxidative damage inside the cells (think free radicals), and to modulate, in a health-promoting way, the production of energy inside the cells’ powerplants, the mitochondria. Here are a few of the relevant details. They activate pathways involving AMPK (adenosine monophosphate-activated protein kinase), the enzyme which acts like a cellular energy sensor, ditto with the sirtuins, which function like cellular repair crews. They keep the body’s mTOR system in balance, making sure more of the body’s resources go to maintenance and less to growth, exactly what we want once we’ve reached mature adulthood.
What’s the take-away from all this scientific detective work? CRMs have been shown to extend lifespan and healthspan in animals, and human studies suggest they can help us prevent and manage age-related diseases, especially degenerative brain diseases, as well as improve cognitive function.
The ones we talk about most in the longevity world include a few you’ve likely heard of, and a few that may be news to you. Among the most promising CRMs:
- Metformin – this widely used and well-tolerated diabetes drug can decrease the expression of ‘chaperones,’ proteins that can interfere with the necessary cell death process (aka apoptosis) and promote tumor growth. Metformin has been shown to extend lifespan and reduce the incidence of mammary tumors in mice. It also mimics the effects of CR by reducing body temperature and insulin levels. It also upregulates proteins responsible for the care and feeding of your neurons – “neurotrophic factors” -- protecting brain health.
- Spermidine – like CR, it helps cells stay more youthful by promoting autophagy, the clean-up process that recycles old cell parts in the service of improved physiological function, plus it has anti-inflammatory properties.
- Polyphenols – the largest family of compounds found in the plants we eat, are effective CRMs because they activate cellular pathways like AMPK, SIRT1 and NRF2, which enhance stress resistance, improve metabolism, and promote longevity. They also reduce oxidative damage and chronic inflammation, key factors in aging and age-related diseases.
- Resveratrol – found in grape skin, it’s been shown to increase lifespan in various animal species. It impacts stress signaling pathways, enhances dopamine action, and, like metformin, gives a boost to those brain-protective “neurotrophic factors.”
- Curcumin – activates key pathways like AMPK and SIRT1, which are involved in cellular energy regulation and longevity, similar to the effects seen with CR. It also reduces inflammation and oxidative stress, both major contributors to aging and metabolic decline.
- Quercetin – a flavonoid found in many fruits and vegetables, activates AMPK and modulates pathways like SIRT1 and FOXO, which are crucial for cellular stress resistance and longevity. It also reduces oxidative damage and inflammation, mimicking the beneficial effects of CR without reducing food intake.
- Fisetin – another flavonoid found in a number of fruits and vegetables, also activates key longevity pathways like AMPK and SIRT1, while promoting the clearance of senescent cells as well. It reduces inflammation, oxidative stress, and supports mitochondrial function, all effects associated with CR.
- Ketones – particularly β-hydroxybutyrate (BHB), act as CRMs by activating many of the same cellular pathways triggered by fasting, such as enhancing mitochondrial function, promoting autophagy, and reducing inflammation. They are also histone deacetylase (HDAC) inhibitors, which have a positive effect on a number of the hallmarks of aging.
That’s quite a list but know that other compounds are actively being investigated for CR-like properties as well, including theaflavins (found in black tea), hesperidin, ginkgo biloba, pterostilbene, pyrroloquinoline quinone (PQQ), rapamycin, nicotinamide riboside, cinnamon, and medium-chain triglycerides, just to name a few.
Looking at the CRM road ahead.
While all of the emerging CRMs show potential as disease-fighters, especially against the most common diseases of aging, the research is still very much a work-in-progress. More studies are needed to fully gauge their long-term effects. What we do know, in a general sense, is that CRMs work in four longevity-promoting ways: by activating autophagy; helping modulate our metabolic pathways; improving mitochondrial health; and modulating our stress response. When we understand these compounds more fully, we’ll be able to optimize their therapeutic use and we’ll be that much closer to that mythical fountain of youth that our ancestors could only dream about. And finally, as much as these CRM’s could be helpful, eating a healthy diet with time restricted eating and exercising, should always be a priority.
