Aging & Longevity

Nutrition For Longevity: Optimizing Lifespan Through Dietary Choices

Nourishing the body with healthy dietary choices, including caloric restriction, time-restricted feeding, and plant-based diets enhances overall well-being and promotes longevity.

By Dylan G. Arrazati
  1. Fasting: Caloric Restriction
    1. How Does Caloric Restriction Promote Longevity?
      1. Inhibits mTOR
      2. Activates AMPK
      3. Boosts NAD+ and Sirtuins
      4. Circadian Rhythm
  2. Time Restricted Feeding
    1. Fasting-Mimicking Diet
  3. Dietary Strategies
    1. Reducing Sugar Intake
    2. Choosing the Right Carbs and Fats
    3. Vegetarian and Mediterranean Diet

You may have noticed that some individuals look older than others despite being the same age. Since our genetics account for only 25% of the variation in human longevity, we have a great deal of control over how fast we age. We can’t stop the aging process, but we can attempt to slow it down or even reverse it. There are lifestyle choices we can make to reduce the chances of succumbing to age-related diseases, and these choices can potentially lead to a longer life. With aging research booming over the last few decades, scientists’ studies have again and again supported the benefits of healthy dietary regimens while shedding light on particular lifestyle habits conducive to healthy aging that are not as well known. 

Fasting: Caloric Restriction 

It’s no surprise that what we eat contributes heavily to how we age, and determining the right foods is no easy task. However, it may not be what we eat but how much we eat that matters, as the dietary strategy shown to be most beneficial to longevity is caloric restriction (CR) – limiting calories without malnourishment. Many studies have shown that caloric restriction increases the lifespan of various model organisms, including yeast, worms, fruit flies, and rodents. 

In humans, caloric restriction has been shown to reduce inflammation, which underlies many age-related diseases. Interestingly, longevity enthusiast and science entrepreneur Bryan Johnson has incorporated CR into his aging optimizer routine (Blueprint), which likely has contributed to slowing his rate of aging to that of a 10-year-old. 

Inflammatory Response Modulation by PLA2G7. The diagram illustrates the role of PLA2G7 in mediating inflammatory responses. Caloric restriction suppresses the PLA2G7 gene, resulting in enhanced thymus function and reduced inflammation.
(Spadaro et al., 2022 | Science) The PLA2G7 Mediates Inflammatory Response. Caloric restriction inhibits the PLA2G7 gene leading to increased thymus function and decreased inflammation. 

How Does Caloric Restriction Promote Longevity? 

Inhibits mTOR

One of the primary known benefits of caloric restriction is the inhibition of the nutrient-sensing complex mTOR (mammalian target of rapamycin), a key modulator of cellular growth and protein synthesis. Suppressing mTOR has led to increased lifespan in various model organisms, suggesting that mTOR inactivation is largely responsible for CR’s effects on longevity. However, some studies found that the life-extending effects of mTOR are tied to reduced growth, highlighting a potential trade-off of CR. 

That being said, mTOR inhibition has been shown to activate a key anti-aging process known as autophagy – the removal of cellular waste – which has been shown to hamper many age-related conditions in animal models, especially neurodegenerative disease. What makes autophagy particularly important to longevity is its role in regulating mitochondrial homeostasis. Studies have repeatedly shown that clearing out defective mitochondria via autophagy is crucial to healthy cellular energy metabolism and helps mitigate oxidative stress, inflammation, and mitochondrial dysfunction, all of which are hallmarks of aging. Notably, boosting autophagy has been linked to delayed cardiac and skeletal muscle aging, demonstrating that mTOR inhibition via CR is a promising intervention to protect against these harmful diseases. 

Roadmap of mTOR Inhibition. The visual outlines a roadmap depicting the process of mTOR (mechanistic target of rapamycin) inhibition, a crucial cellular pathway involved in various biological functions.
Roadmap of mTOR Inhibition

Activates AMPK

Caloric restriction essentially tricks the body into going into self-preservation mode by activating survival factors like AMPK. AMPK is an enzyme that senses low energy and, when activated, increases antioxidant defense systems, regulates inflammation, and promotes anti-aging cellular processes like mitochondrial biogenesis – the production of new mitochondria. Upon activation, AMPK also shuts off mTOR, shedding light on a unique dynamic overlap between pathways linked to longevity. So while inhibiting mTOR prolongs lifespan, studies show that promoting AMPK activity prolongs lifespan. Although CR effectively activates AMPK, humans can also naturally amplify AMPK activity through regular exercise or treatment with metformin; however, this drug is typically prescribed to treat diabetes and AMPK can be activated by natural molecules like berberine and quercetin

Boosts NAD+ and Sirtuins

Another benefit of caloric restriction is that it elevates circulating nicotinamide adenine dinucleotide (NAD+) – a life-preserving coenzyme essential for many fundamental biological processes. NAD+ levels deplete by more than 50% with age, and insufficient NAD+ pools are connected to the progression of multiple age-related diseases, including heart disease and neurodegeneration. Several animal studies have shown that raising NAD+ levels defends against these conditions and can prolong lifespan in cases of disease and aging models, demonstrating another potential mechanism linking CR, NAD+, and longevity.  

Uniquely, NAD+ fuels a family of enzymes called sirtuins, which are important to longevity-associated processes like DNA repair and mitochondrial maintenance. Moreover, sirtuins participate in processes vital to muscle, brain, and metabolic function. In the absence of NAD+, sirtuins stay inactivated, and DNA damage increases, which triggers cellular senescence – a dormant state of cellular arrest that drives aging. Thus, it’s possible that CR’s health benefits stem from its effect on senescent cells. Studies continue to establish the role of sirtuins in longevity, but some evidence suggests that without sirtuins, CR fails to promote increased lifespan in yeast and rodents. Conversely, over-activating sirtuin activity leads to increased lifespan, further highlighting the connection between sirtuins, NAD+, and lifespan. 

For those looking to raise NAD+ levels without implementing daily CR, studies show that taking NAD+ precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) is sufficient to replenish NAD+ levels and stimulate sirtuins. 

Circadian Rhythm

Circadian rhythms, often referred to as our body’s internal or biological clocks, regulate a myriad of metabolic, physiological, and behavioral processes that affect aging. Environmental cues, especially sunlight, play a major role in setting our circadian rhythms, but when we choose to eat can also have an effect on our biological clocks. Namely, aligning feeding times with active waking time (during the day when the sun is out for humans) has been shown to enhance the benefits of CR in mice

While the relationship between CR and circadian rhythms warrants further investigation, the current data suggest that CR may not incur longevity-promoting benefits without functional circadian clocks. Studies have identified two master clock genes (Bmal1, Clock) that serve as master switches and control the expression of other genes in response to internal or environmental cues. Researchers have shown that mice lacking Bmal1 fail to live longer following CR, suggesting that having a fine-tuned circadian clock is necessary for CR to prolong lifespan. 

Lifespan Extension through Nighttime Caloric Restriction. The image demonstrates the effects of different caloric restriction strategies on mouse lifespan. Compared to mice with unrestricted diets (AL – ad libitum), calorically restricted (CR) mice show varying increases in lifespan: CR-spread (no fasting) 10.5% longer, CR-day-12h (12-hour daytime feeding) 18.9% longer, CR-day-2h (2-hour daytime feeding) 21.1% longer, CR-night-12h (12-hour nighttime feeding) 33.6% longer, and CR-night-2h (2-hour nighttime feeding) 34.8% longer.
(Acosta-Rodriguez et al., 2022 | Science) Nighttime Caloric Restriction Increases Lifespan Further than Daytime Caloric Restriction. Compared to mice fed an unrestricted diet (AL – ad libitum), calorically restricted (CR) mice with no feeding window/fasting (CR-spread) lived 10.5% longer, mice fed within a daytime 12-hour feeding window (CR-day-12h) lived 18.9% longer, mice fed within a daytime 2-hour window (CR-day-2h) lived 21.1% longer, mice fed within a nighttime 12-hour window (CR-night-12h) lived 33.6% longer, and mice fed within a nighttime 2-hour window lived 34.8% longer.

Time-Restricted Feeding

It’s important to note that limiting caloric intake is just one method of fasting that harnesses the health benefits of mTOR inhibition. Harvard aging scientist Dr. David Sinclair has continually touted the benefits of time-restricted feeding (TRF) – a form of fasting whereby daily calories are consumed within an eight-hour period. Indeed, data has shown that TRF increases the lifespan of mice, especially when combined with caloric restriction. TRF also elevates beneficial molecules secreted by gut bacteria in mice, which leads to improved blood glucose levels and fat metabolism. Moreover, some human studies have found that TRF helps blood pressure, decreases oxidative stress, and enhances cardiovascular function.  

However, TRF has its own restrictions, as feeding restricted to daylight hours increases fly lifespan, but feeding outside of these hours reduces lifespan, again highlighting the interplay between circadian clocks and dietary intervention. Indeed, according to a mouse study, it seems that fasting for extended periods of time is more beneficial to increasing lifespan than caloric restriction alone. Another method for caloric restriction called intermittent fasting (IF) — not eating for longer than a day — improves age-related frailty and cognition in mice. In humans with diabetes or obesity, IF has been shown to lower overall fat mass and attenuate insulin resistance. 

Fasting-Mimicking Diet

If dietary restriction isn’t something that fits your lifestyle, a fasting-mimicking diet may be the answer. The fasting-mimicking diet involves lowering mTOR by reducing the consumption of branched-chain amino acids. The branched-chain amino acids (leucine, isoleucine, and valine) can be found in high amounts in protein-rich foods like red meat, milk, and eggs. Limiting these foods could decrease mTOR activation.

If dieting just isn’t your thing, it may be worth trying so-called caloric restriction mimetics — supplements that mimic the benefits of caloric restriction. One candidate for such a mimetic is rapamycin, an FDA-approved drug that inhibits mTOR. Rapamycin can even be combined with dietary restriction, as a study in fruit flies found that combined treatment with rapamycin and a restricted diet led to lifespan increases that were greater than individual treatments alone. Notably, while dietary restriction and rapamycin both inhibit mTOR, studies have shown that each intervention traverses a unique but overlapping set of metabolic pathways linked to aging. This means that combining both regimens could potentially target a wide variety of age-related conditions. Currently, there’s an ongoing clinical trial (NCT04488601) evaluating rapamycin’s longevity-boosting effects in healthy older adults.

Dietary Strategies

While fasting and caloric restriction have been found to increase the lifespan of model organisms, it’s difficult for many of us to follow and sustain such restrictive protocols for extended periods of time, let alone a lifetime. Therefore, an alternative would be to simply make dietary choices associated with increased lifespan and reduced disease in humans. If anything, these dietary strategies can promote weight loss and reverse obesity, which is associated with several age-related diseases like diabetes and heart disease.

Reducing Sugar Intake

One dietary strategy to strive for is eating less sugar. Consumption of too much sugar can lead to type 2 diabetes and possibly heart disease. Sugar also shuts off AMPK and sirtuins, which is counter to the known mechanisms modulating increased lifespan. Thus, eating too much sugar is like lowering your defenses against disease and aging.

Health Consequences of High Sugar Consumption. The graphic illustrates health problems associated with elevated sugar intake, including cardiovascular disease, diabetes, cancer, dental caries, obesity, and impaired cognitive function.
(Arshad et al., 2022 | Heliyon) Health Issues Linked to Increased Sugar Consumption: Cardiovascular Disease, Diabetes, Cancer, Dental Caries, Obesity, Impaired Cognition

Choosing the Right Carbs and Fats

Although carbohydrates are the body’s primary energy source, it’s important to note that not all carbs are created equal. When it comes to choosing the right carbs, health experts encourage individuals to avoid refined carbohydrates – carbs that have undergone extensive processing and refinement. In addition to lacking the nutrients and minerals necessary for cellular function, nutritionists also point out that refined carbohydrates fail to provide long-lasting energy because digestive enzymes break them down much more quickly, which can ultimately lead to overeating due to the increased feeling of hunger. 

To provide the body with a steady release of energy, individuals should instead consume unrefined carbohydrates, which are digested much more slowly due to their complex and unrefined structures. These healthier carbs, which are rich in essential nutrients like fiber, vitamins, minerals, and antioxidants, can be found in whole foods such as fruits, whole grains, vegetables, and legumes. 

Consuming the right fats is also paramount to one’s health and overall well-being, and research indicates that individuals should limit their intake of saturated and trans fats, which are found in meat products, cheese, ice cream, and some vegetable oils. What makes saturated and trans fats particularly bad is their ability to raise bad (LDL) cholesterol, which drives inflammation and significantly increases the risk of harmful conditions like heart disease and diabetes. 

To help avoid these abnormalities, health experts recommend people stick to unsaturated fats (monounsaturated, polyunsaturated), which are found in foods like nuts, seeds, oily fish, and avocados. One particular polyunsaturated fat with brain-boosting and anti-inflammatory properties is docosahexaenoic acid (DHA), commonly known as omega-3 fatty acids. Accordingly, eating eight ounces of oily fish like salmon every week can help replenish this vital nutrient, which naturally declines with age. 

Vegetarian and Mediterranean Diet

A 2013 study showed that vegetarians live longer than non-vegetarians. Another study showed that the Mediterranean diet decreased biological aging. The Mediterranean diet consists mostly of plant foods but also includes some fish. These diets, high in plant-based foods, may be good for us because they are rich in molecules called polyphenols, which activate sirtuins.

Similar to the vegetarian and Mediterranean diet is the Sirtfood Diet. This diet specifically incorporates foods that are high in polyphenols to activate sirtuins. Many celebrities have used this diet to shape up quickly, like musical artist Adele and UFC fighter Conor McGregor.

Representation of Polyphenols. The visual portrays polyphenols, a group of natural compounds found in plants, known for their antioxidant and potentially beneficial health effects.
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