Aging is really not that complicated once you understand the genes that control it,” says David Sinclair, a top longevity researcher at Harvard Medical School.
Good news. Because, as Sinclair claims on his Longevity podcast, genes have the power to defend against aging.
Control them, and you can improve your healthspan and lifespan—a reality the founder of Tally Health has experienced firsthand. Even though Sinclair’s ID pegs him as 53 years old, the results of his biological age test claim he’s only 42.
How? Alongside regular exercise and an impressive supplement stack, improving his nutrition helped Sinclair turn back the clock. Here’s exactly how David Sinclair eats to optimize his genes for a healthier, longer life.
Eat for Your Genes
“Part of the problem with aging is that you start to get this unspooling of DNA, and genes that shouldn’t be on are on,” says Sinclair. How and when you eat should be aimed at correcting the course of these wayward genes, according to Sinclair. Specifically three genes: mTOR, AMPK, and sirtuins. Here’s a quick crash course.
Sirtuins are a family of longevity genes. “This family has been shown to be a really important central regulator of longevity,” Sinclair says. Studies have shown that sirtuins play a key role in cell response to a variety of stressors—such as oxidative or genotoxic stress—and are crucial for cell metabolism (1).
You might remember sirtuins from infamous research that emerged from Sinclair’s lab in the early 2000s—which uncovered red wine might actually be good for you. The research discovered that the polyphenol resveratrol, found in red wine, activates the sirtuin SIRT-1 (2).
Interestingly, sirtuins are activated by stress. “Fasting activates sirtuins, exercise activates sirtuins—the generic things that doctors tell us to do, we believe are mediated through sirtuins,” explains Sinclair.
When you eat protein, the mammalian target of rapamycin (mTOR) gene is activated. mTOR is responsible for regulating protein production and directly influences cell growth, division, and survival.
“When you eat a big steak, mTor is activated,” Sinclair says. “And that’s why you build up more muscle than if you don’t eat a lot of protein.”
Great, right? Nope. A certain degree of muscle mass is important for longevity (3), and Sinclair specifies we do need protein to thrive; however, too much mTOR is linked to age-related diseases like diabetes and cancer (4, 5).
“If you downregulate the activity of this mTOR protein complex, you get longer life,” Sinclair explains, “because it’s activating a process called autophagy, which recycles proteins.” A process that enhances cell performance, keeping you healthy.
Adenosine 5’ monophosphate-activated protein kinase (AMPK) is an enzyme known as the body’s master regulator of energy metabolism.
“One of the main things that [AMPK] does is it makes more mitochondria. We lose mitochondria as we get older,” Sinclair says. Poor mitochondrial function is linked to heart disease (6), dementia (7), type 2 diabetes (8), metabolic syndrome (9), and insulin resistance (10).
“Mitochondria are important for metabolizing what we eat and making chemical energy,” Sinclair says. “That’s why when you activate AMPK you’ll have more energy, and feel better.”
“AMPK also sits as a central regulator of the body’s defenses,” explains Sinclair. “It will downregulate mTOR, and activate other longevity genes. These genes are working in concert with one another.”
AMPK is linked to blood sugar. When cells are starved of glucose, like when fasting, AMPK is activated. This can be replicated with Metformin—a drug used to treat type 2 diabetes that can lower levels of glucose in the body, enhance insulin sensitivity, and reduce symptoms of aging (11). Exactly why Metformin is the star subject of ongoing clinical trials on anti-aging (12, 13).
When to Eat
According to Sinclair, eating less often can help optimize your genes. “It’s not just about the period of eating, it’s the period of not eating that’s so important to boost the body’s defenses against aging to maximize longevity,” he says.
Why? Stress from fasting triggers an optimal metabolic shift in your genes—upregulating sirtuins and AMPK, and downregulating mTOR. Fasting is associated with improved outcomes for people with metabolic syndrome (14), prediabetes (15), diabetes (16), multiple sclerosis (17), and breast cancer (18).
According to Sinclair, there’s not one right way to fast. “You’re an individual, you’ve got a different lifestyle, tolerance for pain and hunger, and microbiome—these are really important things to take into consideration,” he says. He recommends trying one of the three fasting methods, below.
Extended fasting is any period longer than a day— people go one day, three days, and others, like Peter Attia, a week.
“These extended periods are going to do a real deep clean of the body and turn on that autophagy. Especially once you pass the three-day mark, when your metabolism switches into what’s called chaperone-mediated autophagy (20)—also known as the deep cleanse,” he explains.
The most practical of Sinclair’s suggested fasting protocols, and the one he follows involves eating during a specific time block of the day and fasting for the rest. Popular time-restricted feeding protocols include 18:6 intermittent fasting—where you fast for 18 hours and eat for 6—and 20:4—where you fast for 20 hours and eat for 4.
“You want to have at least 16 hours of not eating or not eating very much,” says Sinclair. “So typically that means having a late lunch if you skip breakfast, or if you prefer to skip dinner, you can skip that.”
When you fast, your liver compensates for the lack of food by initiating gluconeogenesis—a process where the liver transforms lactate, amino acids, and glycerol into glucose for energy. After several weeks of regular intermittent fasting, your liver will start making glucose at a steady level, effectively avoiding the rise and fall of glucose that happens when you eat regular meals throughout the day.
The “fasting-mimicking diet” was developed by Valter Longo, a researcher out of UCLA. His work found that a fasting-mimicking diet helped cancer patients survive and get over chemotherapy faster (19).
The diet is perfect for people who want the benefits of fasting but don’t want to give up food entirely. It involves severely restricting your calories (to 1,100 calories per day) for five days a month. During which, you focus on eating plant-based, whole foods that are low in carbs and protein, and high in healthy fats.
This specific nutrient profile (when delivered in precise quantities) mimics your body’s physiological response to traditional fasting. According to Sinclair, the secret sauce is in eating less meat, which suppresses mTOR.
To follow the diet, whip up longevity recipes directly from Longo’s kitchen or try ProLon—a service Longo developed to have everything you need to follow a five-day mimicking fasting diet delivered straight to your doorstep once a month.
Fast Like Sinclair
Sinclair claims his fasting practice has helped him shed 15 pounds and get his twenty-year-old body back—which he sees as just an added bonus to the longevity benefits.
- He follows a 20:4 fasting schedule where he tries not to eat until dinner and then has a “really enjoyable, big dinner”.
- He drinks a lot of water throughout the day, which helps reduce his feeling of hunger, and when he absolutely needs to snack on something he reaches for a small handful of nuts.
- He mixes a little bit of yogurt with his supplements to dissolve them. Pairing fat-soluble vitamins (A,D,E, and K) with fat can help with absorption.
- He drinks Athletic Greens in the morning to compensate for some of the potentially missed nutrients from fasting that may help him function earlier in the day.
What to Eat
Fasting is typically more about when you eat rather than what you eat. However, fasting—especially when performed for longevity—works best with a healthy diet, per Sinclair. “Adequate nutrition is necessary, because otherwise you’re going to be doing your body more harm than good,” says Sinclair.
What exactly does that entail? For Sinclair, the focus is eating more of just one type of food to live longer: plants.
According to Sinclair, the more plants you eat the better. He specifically recommends focusing on plant foods with polyphenols like berries, red wine, matcha, olives (and olive oil), beans, and vegetables like artichokes, chicory, red onion, and spinach.
Why? Polyphenols, like resveratrol, piceatannol, fisetin, and quercetin activate sirtuins.
Interestingly, the more you stress a plant, the more polyphenols they make to help them survive. That’s why foods that are intentionally stressed, like red wine, are rich in polyphenols. “The best red wines are ones where the vines are dehydrated or have fungus growing on them. There’s a good reason for that,” says Sinclair. (Pro tip: if you’re a wine lover, choose pinot noir—per Sinclair, it’s the highest in resveratrol, the active polyphenol).
The record scratch: in our food supply, our plants don’t experience much stress. Sinclair explains plants grown bigger and faster are more profitable for farmers; but, aren’t likely to contain polyphenols.
How to know if your food is being stressed? “Well, you can start with the generalization that if they’re grown out in a field organically, without pesticides, they’re probably more stressed,” Sinclair explains. “What I look for are plants that are organic, local, and colorful, because those are the most likely to be rich in these molecules.”
What Not to Eat
Sinclair’s list of foods not to eat is slightly longer. However, he’s clear your diet should not be restrictive and include adequate amounts of macronutrients to fuel your body for life (and quick to admit he eats his fair share of dessert). However, these two foods can wreak havoc on your genes when eaten in excess. Here’s the scoop.
At a high level, glucose shuts off your body’s protective mechanisms—AMPK and sirtuins. To avoid this unfavorable shift, Sinclair recommends eating less sugar and aiming to keep glucose levels consistent.
“If you’re eating three meals a day plus snacks, your glucose will spike, and your defenses against aging are going to be working at a minimum,” explains Sinclair. He recommends monitoring glucose levels with a continuous glucose monitor and adjusting your diet accordingly to minimize spikes.
“Certainly if you’re an athlete, or want to bulk up, there are short-term gains to eating meat,” he says. “You’ll feel better if you eat meat, you’ll have the protein to build up that muscle.” In these cases, you need more protein to sustain high levels of activity, and activating mTOR plays an important role in building muscle.
While that’s good in the short term, according to Sinclair, “mTOR can do something even better for longevity in the long run by being downregulated and activating autophagy.” He notes mTOR can be activated sometimes, but you don’t want it activated all the time.
By giving your body a periodic break from processing amino acids—particularly BCAA’s (leucine, isoleucine, and valine) which activate mTOR—you’ll give your body a chance to tap into autophagy. This doesn’t mean you need to give up meat, Sinclair suggests intermittent fasting is enough to downregulate mTOR.
Eat Like Sinclair
Sinclair focuses on a Mediterranean diet packed with lots of fruits and veggies. Here’s how he breaks it down.
- He doesn’t eat meat, opting to get his protein from plant sources.
- He shops for organic, local, colorful fruits and vegetables which are most likely to be packed with polyphenols.
- He cooks with olive oil to activate sirtuins.
- He avoids sugar and leans on sugar-free alternatives to add sweetness to his food.
- If he does eat sugar, he eats it at the end of the meal to reduce glucose spikes.