Aging & Longevity

David Sinclair: How to Change Your Diet to Live Longer

In the second podcast based on his book LifeSpan, Dr. Sinclair talks about the science behind how fasting and eating certain foods promote longevity.

By Daniel R. Miranda, Ph.D.


In the second podcast episode of Lifespan with Dr. David Sinclair, he and co-host Matthew LaPlante discuss how we can live longer by changing the way we eat. They guide listeners towards a path to longer living by examining how we can change our eating habits to live longer, all while explaining the relevant science. 

Less Calories, Longer Life

If three words could sum up how to live longer by changing our eating habits, Dr. Sinclair would say, “eat less often.” This does not necessarily mean consuming fewer calories but packing in the calories within a shorter period. In fact, we need calories to avoid malnourishment and starvation. 

Why eat less often? For Sinclair, it started with a study showing that the lifespan of dogs could be increased by reducing their caloric intake. This study inspired Dr. Sinclair to pursue his research on aging, where he has since found similar results in yeast. “There’s a genetic pathway that gets triggered by low energy,” says Sinclair. We consume less energy and activate enzymes called sirtuins by consuming fewer calories. 

Longevity-Related Molecules: Sirtuins, mTOR, and AMPK  

At his lab at Harvard Medical School, Dr. Sinclair and his team found that low energy activates sirtuins by causing our cells to make NAD+ (nicotinamide adenine dinucleotide), which sirtuins use as fuel. NAD+ was shown to increase the lifespan of yeast, which is one of the reasons why so many people now take NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) supplements, which boost NAD+ levels. 

In addition to sirtuins, another molecule important for longevity is mTOR (mammalian target of rapamycin), except this one is better if not activated. Many animal studies show that decreasing mTOR increases lifespan. Sinclair explains that this is due to autophagy, where old proteins are recycled to make new ones. In humans, drugs that inhibit mTOR, like rapamycin, boost immunity and cause biochemical changes that mimic fasting and predict longevity.

The final longevity molecule discussed by David and Matthew was AMPK (AMP-activated kinase), an enzyme that goes up in response to low energy. One function of AMPK is to make more mitochondria, which decrease as we age and are vital for cell survival. In humans, the type 2 diabetes drug metformin activates AMPK and has been shown to reduce age-related disease. 

Fasting to Control Longevity-Related Molecules 

We must fast to eat less often and regulate sirtuins, mTOR, and AMPK. Dozens of human studies have shown that fasting is beneficial for longevity. A Baylor College of Medicine study showed that fasting improved blood pressure, reduced BMI, decreased weight circumference, and, “importantly,” Sinclair says, upregulated DNA repair proteins. He explains that diseases like type I diabetes, multiple sclerosis (MS), and even cancer benefit from fasting. 

“Those three defense components [sirtuins, mTOR, AMPK] of the cell take care of the body, not just for aging, but to fight diseases in young people, middle-aged, and genetic diseases,” says Dr. Sinclair. 

(Mindikoglu et al., 2020 | Scientific Reports) Baylor College of Medicine Study. Fasting from dawn to sunset for 4 weeks increases DNA repair and proteins associated with prolonged longevity while decreasing weight, body mass index (BMI), and insulin resistance. 

How Should We Fast?

David and Matthew go over three primary ways of fasting: the fasting-mimicking diet, intermittent fasting, and time-restricted feeding. 

The fasting-mimicking diet involves lowering mTOR activity by reducing the consumption of branched-chain amino acids. For this diet, the time window for eating isn’t as rigorous. Sinclair says, “you want the body to be in a state of perceived adversity.” He explains that in a clinical trial, the fasting-mimicking diet was shown to help cancer patients survive and get over chemotherapy quicker. 

Intermittent fasting is going longer than a day without eating. This can go on for days or weeks, although Dr. Sinclair says, “he wouldn’t go longer because you’ll start chewing up your muscle.” These long fasts turn on autophagy. “Once you’ve gone beyond three days, your metabolism switches into what’s called chaperone-mediated autophagy, the deep cleanse.” 

Time-restricted feeding, which involves not eating for at least 16 hours within 24 hours, is Dr. Sinclair’s preferred fasting method. Sinclair explains that your liver will start making glucose at a steady level after a few weeks, so there won’t be large spikes of insulin that put you in a glucose deficit and make you tired. 

Which fasting method is best? David and Matthew proclaim the importance of genetics when it comes to fasting. A mouse study showed that caloric restriction shortened the lifespan of more mice (based on genes) than it lengthened. This means that caloric restriction probably does not work for everybody. Sinclair also says that fasting isn’t easy, but it’s worth it. The trick, he says, is to fill yourself with fluids. 

“For me, constant coffee, tea, hot water, all the way through the day. Being hydrated and filled with liquid takes away any feeling of hunger.” 

What To and Not To Eat?

In the last portion of the conversation, David and Matthew go over what we should eat to live longer. First, they go over what not to eat: sugar and meat. 

Dr. Sinclair says that sugar is bad because it will reduce longevity, lead to type 2 diabetes, and possibly cause cardiovascular disease. It also shuts off AMPK and sirtuins. In other words, with high sugar, your defenses against disease and aging are minimal. 

The Harvard scientist explains that red meat is non-beneficial. It is suitable for athletes or bulking up, but when looking at the evidence, high protein, carnivorous, red meat-based diets are not beneficial for a longer lifespan. High protein will shut off sirtuins, and the branched-chain amino acids in meat activate mTOR, inhibiting autophagy. 

What should we eat? Dr. Sinclair himself is now a vegetarian if that tells you anything. Also, in the 2013 Adventist Health study, it was calculated that vegetarians live longer than non-vegetarians. Additionally, in a study on women, the Mediterranean diet (mostly vegetarian with some fish) decreased biological aging. 

“That fasting or eating the right foods, like the Mediterranean diet not just to slows down the ticking of the clock, but probably reverses your age is a mind-blowing concept,” says Dr. Sinclair. 

Why are plant-based foods good for us? Dr. Sinclair and Dr. Konrad Howitz published a paper in Nature showing that plants contain molecules called polyphenols, which activate the sirtuin enzyme Sirt1 and cellular pathways important for health and longevity. 


As told by Dr. Sinclair, the takeaways of this podcast are to (1) eat less, (2) avoid sugar, (3) reduce meat intake, and (4) eat more of a plant-based diet, like the Mediterranean diet.  He mentions that a study of elderly subjects in Spain showed that you could change your diet until the age of 80 and still get the benefits, so it’s not too late for many of us to change our eating habits to help us live longer lives.


Sinclair, David. “Lifespan with Dr. David Sinclair | What to Eat & When to Eat for Longevity.”, January 12th, 2022,

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