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LifeXtenShow – The Stress of Eating Less

We discuss what caloric restriction is and why it works.

X10 Caloric Restriction ThumbnailX10 Caloric Restriction Thumbnail
 

In this episode of X10, we discuss the practice of caloric restriction along with its effects, which involve the TOR signaling pathway, epigenetic alterations, and DNA repair.

Sources

Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. doi: 10.1126/science.1173635

Cooper TM, Mockett RJ, Sohal BH, Sohal RS, Orr WC. (2004) Effect of caloric restriction on life span of the housefly, Musca domestica. The FASEB Journal. doi: 10.1096/fj.03-1464fje

Dang W, Sutphin GL, Dorsey JA, Otte GL, Cao K, Perry RM, Wanat JJ, Saviolaki D, Murakami CJ, Tsuchiyama S, Robison B, Gregory BD, Vermeulen M, Shiekhattar R, Johnson FB, Kennedy BK, Kaeberlein M, Berger SL. (2014) Inactivation of Yeast Isw2 Chromatin Remodeling Enzyme Mimics Longevity Effect of Calorie Restriction via Induction of Genotoxic Stress Response. Cell. doi: 10.1016/j.cmet.2014.04.004

Forster MJ, Morris P, Solah RS. (2003) Genotype and age influence the effect of caloric intake on mortality in mice. The FASEB Journal. doi: 10.1096/fj.02-0533fje

Ke Z, Firsanov D, Spencer B, Seluanov A, Gorbunova V. Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice. (2020) Aging and Mechanisms of Disease. doi: 10.1038/s41514-020-00047-2

Li Y, Daniel M, Tollefsbol TO. Epigenetic regulation of caloric restriction in Aging. (2011) BMC Medicine. doi: 10.1186/1741-7015-9-98

Maegawa S, Lu Y, Tahara T, Lee JT, Madzo J, Liang S, Jelinek J, Colman RJ, Issa JPJ. (2017) Caloric restriction delays age-related methylation drift. Nature Communications. doi: 10.1038/s41467-017-00607-3

Wei M, Fabrizio P, Hu J, Ge H, Chenc C, Li L, Longo VD. (2008) Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9. PLoS Genetics. doi: 10.1371/journal.pgen.0040013

The NIA on this subject

Script

It’s great that scientists are learning more about aging and finding potential therapeutic targets, but you’re probably more interested in things that can help now. Has all this research produced any tools that we can already use to live longer?

The bad news is that we haven’t found the fountain of youth or discovered a drug that can stop us from getting old. But there is a simple change that does the trick in lots of different creatures: caloric restriction. Let’s dig in and find out what it’s all about!

Welcome to X10, your one-stop YouTube show for all things life extension. Learn the science, keep up with new research, and live longer and healthier. To get updates from X10, click the red button below to subscribe, and don’t forget to hit the bell icon and select “all notifications”.

This is part of a series of videos on diet and longevity. In this episode, I’m going to tell you about caloric restriction.

Caloric restriction is basically just what it sounds like: a diet containing fewer calories than normal. In experiments with rats and mice, “fewer” has generally meant something like half to three-quarters of the unrestricted diet.

It’s important to point out that caloric restriction isn’t the same thing as intermittent fasting, which you may have heard about. Intermittent fasting is the practice of fasting for long periods between meals but not necessarily changing the amount of calories consumed. So, caloric restriction is about how much you eat, while intermittent fasting is about how often you eat.

It’s also important to be clear that caloric restriction is still supposed to be a balanced diet. The idea is to reduce the number of calories while still providing all the necessary nutrients in the correct proportions.

So, what happens if you pull that off? We know that caloric restriction makes lots of animals live longer. It’s been reported to extend lifespan in yeast, mice, rats, monkeys, and other organisms. But it doesn’t always work. In a study using houseflies, caloric restriction actually shortened lifespan, and another study found that caloric restriction decreased the lifespan of mice when it was started at an older age.

That’s a bit of a mixed bag. From what we know, it’s hard to say how useful caloric restriction is for humans. There are some studies showing that it provides health benefits, but there isn’t enough data at the moment to draw strong conclusions.

We also don’t yet fully understand how caloric restriction affects lifespan. There’s evidence that it works through several different pathways — which is just a fancy way of saying it’s complicated and scientists are still working out all the pieces.

One of the pathways affected by caloric restriction is genes related to the TOR signaling pathway, which responds to nutrient status. To find out more about TOR and nutrient signaling, check out our video on the deregulated nutrient sensing hallmark.

Work in yeast showed that caloric restriction reduced the level of TOR signaling genes. This made the yeast live longer, but that life extension depended on the activity of several stress response genes. By deleting some of the genes in these pathways and putting the yeast on a CR diet, researchers managed to increase the yeast’s lifespan by ten times!

Caloric restriction also causes epigenetic changes. Studies in rats, fruit flies, and other organisms have found changes in DNA methylation and histone modifications as a result of caloric restriction. If you’d like to know more about how epigenetics is linked with aging, check out our epigenetics series. The idea here is that caloric restriction somehow helps prevent epigenetic changes that cause our genes to be expressed incorrectly as we age.

As though that weren’t enough, a couple of recent studies have linked caloric restriction with DNA repair. A 2014 study in yeast found that caloric restriction requires the ISW2 gene in order to extend lifespan. They showed that caloric restriction reduces the level of ISW2, which leads to higher levels of a gene called RAD51. RAD51 is involved in DNA repair, leading the team to hypothesize that caloric restriction improves the response to “genotoxic stress”. That’s consistent with a more recent paper, which reported that a brief period of caloric restriction in mice improved their cells’ ability to repair DNA breaks.

So, should you restrict your caloric intake to live longer? Well, the evidence isn’t really clear at this point. For example, the NIH webpage says there is “insufficient evidence to recommend any type of calorie-restriction or fasting diet”. It also highlights the importance of getting enough nutrition and talking with a healthcare professional if you’re tempted to try it anyway.

That’s it for our overview of caloric restriction and aging. Check in again next time to learn about intermittent fasting. If you’d like to get notified about that and stay on top of new X10 videos, subscribe to our channel and remember to click the bell icon. You can also like the video and share it with your friends if you learned something new.

And finally, a big thanks to the Lifespan Heroes, who make this show possible through their crowdfunding support. If you’d like to become a Lifespan Hero to support X10 and Lifespan.io, head over to lifespan.io/hero and make a pledge.

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