How Eating Less and Fasting Can Keep You Feeling Young and Energized
The Link Between Caloric Restriction and Longevity
Do you ever feel like your body is a smartphone that’s constantly running low on battery?
Between work, social media, and Netflix binges, it’s no wonder we’re feeling more drained than ever. But what if I told you there’s a way to recharge your body and potentially even extend your lifespan?
No, it’s not a fancy new app or a portable charger — it’s caloric restriction and intermittent fasting.
By limiting the number of calories you consume and taking breaks from eating, you’re essentially giving your body a chance to rest and recharge. And just like how a fully charged phone can last longer and perform better, a well-rested body may be able to function better and potentially even live longer.
The mysteries of aging
Aging refers to the gradual and irreversible process of physiological and functional decline that occurs in living organisms over time.
Aging is a complex process that involves a combination of genetic, environmental, and lifestyle factors, and can manifest in various ways, including changes in appearance, reduced physical and cognitive function, and increased susceptibility to disease and injury.
Despite being a natural and unavoidable process, scientists continue to explore ways to slow down or delay the effects of aging through various interventions, including altering your diet.
Introducing dietary manipulations
There are various different forms of calorie restrictions and fasting:
- Calorie Restrictions: Reducing your average daily caloric intake below what is typical or habitual without malnutrition or deprivation of essential nutrients
- Time-Restricted Feeding: Meals are consumed in a certain number of hours; Ex. only eating for 6 hrs of the day.
- Alternate-Day Fasting: Eating is unrestricted every other day but on the other days, no or minimal calories are consumed
- 5:2 Eating Pattern: Unrestricted eating for 5 days and 2 days or restricted caloric intake.
- Periodic Fasting: Caloric intake is restricted for multiple consecutive days but unrestricted for the rest.
Calorie restrictions and intermittent fasting hold promise as effective interventions for improving health and preventing age-related diseases.
Improving Cellular Function
These interventions are believed to work by improving cellular function, reducing oxidative stress and inflammation, and promoting cellular repair mechanisms.
Inflammation
Chronic inflammation has been linked to a variety of age-related diseases, including heart disease, diabetes, and cancer. Long-term inflammation can damage tissues and organs, causing premature aging. Reducing inflammation through lifestyle interventions such as diet may aid in the promotion of healthy aging and the extension of life.
Sugar Metabolism
High blood sugar levels can cause organ damage, including kidney, eye, and nerve damage. This type of damage can build up over time and contribute to premature aging.
The ability to provide energy for cellular processes
Cells require energy to perform a variety of functions, including DNA repair, protein structure maintenance, and the removal of damaged cellular components. Impaired energy production can result in cellular dysfunction and premature aging. Caloric restriction and intermittent fasting are two nutritional interventions that can help improve cellular energy production, promote healthy aging, and extend lifespan.
Maintenance of protein structures
Proteins are necessary components of all cells that perform a variety of functions such as catalyzing chemical reactions, transporting molecules, and providing structural support. Protein structure is critical for their function, and any damage or misfolding can result in cellular dysfunction and aging. Proper nutrition can help in the preservation of protein structure and the promotion of healthy aging.
DNA alterations
DNA damage can build up over time and contribute to early ageing and age-related diseases. DNA repair enzymes and autophagy are two mechanisms used by the body to repair DNA damage.
Oxidative stress
Reactive oxygen species (ROS) are produced during normal cellular metabolism and can damage cellular components such as DNA, proteins, and lipids. This type of damage can build up over time and contribute to the aging process. To protect against oxidative stress, the body has a number of antioxidant defence mechanisms in place, including enzymes such as superoxide dismutase and glutathione peroxidase. Interventions such as calorie restriction, exercise, and antioxidant supplementation can all help to promote good health.
Understanding the Mechanisms of Calorie Restriction on Lifespan
Calorie restrictions work through nutrient and stress-responsive metabolic signalling pathways, including TOR, AMPK, IIS/FOXO, Sirtuins, and autophagy.
The Rapamycin Pathway
Caloric restriction is known to downregulate the Rapamycin (TOR) pathway, which is believed to partially explain its ability to extend lifespan.
The TOR pathway is an important pathway in eukaryotic cells, any cell or organism that possesses a clearly defined nucleus, that regulates growth and metabolism based on nutrient availability, including amino acids. Genetic studies have shown that suppressing or downregulating the TOR pathway can extend the lifespan in model organisms like yeast, worms, flies, and mice.
Activating the TOR pathway too much can be harmful and may contribute to aging and disease. To mitigate this, the TOR pathway is regulated by AMP-dependent protein kinase (AMPK), which senses cellular energy levels. Activation of AMPK while suppressing the TOR pathway can extend lifespan. Genetic studies have shown that AMPK mediates lifespan extension through calorie restrictions.
The AMPK and TOR pathways are like two sides of a coin. Just like how a coin has a head and a tail side, these two pathways are two sides of the same coin of cellular energy metabolism. When one pathway is activated, the other is suppressed, creating a balance between growth and repair.
ILS-FOXO
Growth hormone (GH) is a hormone that promotes growth in mammals by activating a cascade of hormonal signalling pathways, including the insulin/insulin-like growth factor-1 signalling (IIS) pathway. When IIS is activated by GH, it causes a protein called FOXO to move from the nucleus of a cell to the cytoplasm.
When GH/IIS signals are absent or reduced, FOXO moves into the nucleus and activates genes that promote longevity by switching the body’s metabolic status from growth to maintenance. These genes are involved in processes such as cell death, cell cycle arrest, DNA repair, stress resistance, and detoxification.
Calorie restriction is a well-known way to extend lifespan, and it is believed to do so by limiting GH/IIS signalling and activating FOXO transcription factors. Studies suggest that IIS-FOXO signalling is required for the full benefit of calorie-restricted-mediated lifespan extension.
Both calorie restrictions and intermittent fasting have been shown to increase insulin sensitivity, stress resistance, and immune function with reduced inflammation, which are key metabolic and physiological changes attributed to lifespan extension through IIS-FOXO signalling.
Sirtuins
Sirtuins are proteins that act as metabolic sensors, representing the metabolic state of the cell. They require a molecule called NAD+ to function as deacetylases, which are involved in many cellular metabolic pathways. When NAD+ levels increase under nutritional stress, sirtuins are activated.
Deacetylation is a process where an acetyl group is removed from a molecule. In simpler terms, it’s like taking a piece of a puzzle. This process can have important effects on the function of the molecule, like changing how it interacts with other molecules or altering its activity.
Studies have shown that overexpression of sirtuins extends the lifespan in various model organisms, including yeast, worms, flies, and mice. Sirtuins are important for the lifespan extension effects of calorie restriction in animals, and studies have shown that calorie restriction does not extend the lifespan in animals without sirtuins.
Sirtuins are thought to promote longevity by regulating cellular processes such as DNA repair, oxidative stress response, and cellular metabolism, all while improving insulin sensitivity, increasing mitochondrial function, and reducing inflammation.
By activating sirtuins through caloric restriction and other interventions, it’s like turning on the fountain of youth and allowing our cells to stay healthy and vibrant. Sirtuins work to repair DNA damage, reduce inflammation, and improve mitochondrial function — all key factors in promoting longevity.
Autophagy
Autophagy is a cellular process that involves the degradation and recycling of damaged or dysfunctional cellular components. Autophagy helps maintain cellular homeostasis and promotes cell survival during times of stress or nutrient deprivation. It has been linked to various health benefits, including improved insulin sensitivity, reduced inflammation, and increased lifespan.
Caloric restriction is a dietary intervention that has been shown to increase lifespan in various organisms, including mice and monkeys. Studies have shown that caloric restriction can induce autophagy, which may be one of the mechanisms through which caloric restriction promotes longevity.
Autophagy is thought to promote longevity by removing damaged proteins and organelles, reducing the production of reactive oxygen species, and maintaining cellular energy homeostasis, a state of balance among all the body systems needed for the body to survive and function correctly.
Overview
Imagine a construction site where workers are tasked with building a skyscraper. The workers represent the various molecular pathways in the body that impact longevity, while the skyscraper represents healthy aging and longevity itself.
- TOR is like the construction manager who is responsible for coordinating the various workers and ensuring that the necessary materials are delivered on time. When there is an excess of nutrients, TOR is activated and promotes cell growth and division. However, when nutrients are limited (such as during caloric restriction), TOR is inhibited, which activates other pathways that promote longevity.
- AMPK is like the foreman who is responsible for maintaining the energy supply to the workers. When energy levels are low (such as during caloric restriction), AMPK is activated and promotes energy production through various pathways, including autophagy. This helps ensure that the workers have the necessary energy to continue building the skyscraper.
- IIS/FOXO is like the quality control inspector who ensures that the materials used in the construction are of good quality. When nutrients are limited (such as during caloric restriction), IIS/FOXO is activated and promotes the use of high-quality materials (i.e. proteins that are properly folded and functional). This helps ensure that the skyscraper is built to last and does not deteriorate prematurely.
- Sirtuins are like the maintenance crew who are responsible for repairing any damage to the building. When nutrients are limited during caloric restriction, sirtuins are activated and promote DNA repair, reduce inflammation, and help maintain protein structures. This helps ensure that the skyscraper remains functional and does not develop age-related damage.
- Autophagy is like the cleaning crew who are responsible for removing any waste or debris from the construction site. During caloric restriction, autophagy is activated and helps remove damaged cellular components, including misfolded proteins and dysfunctional organelles. This helps ensure that the construction site remains clean and functional.
Together, these molecular pathways work in harmony, just like the construction workers building the skyscraper, to promote healthy aging and longevity through caloric restriction.
Resetting the Master Clock 🕰
Circadian (~24-hour) clocks control various physiological, metabolic, and behavioural parameters via rhythmic transcription of output genes. Misalignment of these internal clocks with environmental cycles affects metabolism, aging, and age-related diseases.
Caloric restriction increases the amplitude of core clocks in mouse livers and flies; This suggests that the circadian clock may play a master role in lifespan extension by controlling most known calorie restriction effectors, such as GH/IGF-1, FOXO, TOR, AMPK, and sirtuins.
This allows us to conclude that fasting and the time and duration of fasting may be more critical than total calorie intake.
To further explain, ad libitum feeding disrupts circadian rhythms in both the central and peripheral clocks, while time-restricted fasting and calorie restrictions can help synchronize and entrain the clocks. Ad libitum feeding implies that animals are allowed to eat as much as they want whenever they want whereas time-restricted feeding is particularly effective in maintaining the circadian rhythms of peripheral clocks. Ad libitum feeding is associated with various age-related diseases and a shorter lifespan, whereas time-restricted fasting can extend the lifespan of various species, and improve healthspan in ways that are consistent with improved circadian rhythms.
Defying Time: Mitigating Age-Related Disease
As mentioned, calorie restrictions and intermittent fasting hold promise as effective interventions for improving health and preventing age-related diseases.
Some of these diseases include:
Diabetes
Elevated insulin and glucose levels are hallmarks of type 2 diabetes and pre-diabetes. Both caloric restriction and intermittent fasting reduce insulin levels, markers of inflammation, and oxidative stress while maintaining immune competency. Various fasting regimes show a significant visceral fat reduction, which has been linked to lower pre-diabetes and type 2 diabetes risk.
Cardiovascular Disease
caloric restriction and intermittent fasting reduce insulin levels, markers of inflammation, and oxidative stress, and improve blood lipid profile and cardiovascular parameters. They have been shown to reduce visceral fat, potentially lowering the risk of cardiovascular disease.
Inflammatory Diseases and the Immune System
Clinical studies in humans have shown that caloric restriction and intermittent fasting can improve insulin levels, markers of inflammation, and oxidative stress while maintaining immune competency. Studies suggest that caloric restriction and intermittent fasting can improve symptoms of asthma, multiple sclerosis, and arthritis.
Cancer
Caloric restriction and intermittent fasting seem to bear anti-neoplastic potential, but decisive clinical trials are rare and urgently needed. Antineoplastic drugs are medications used to treat cancer. Caloric restriction and intermittent fasting as well as short-term fasting, make cancer cells more sensitive to chemotherapy. This means that these dietary interventions could potentially improve the effectiveness of chemotherapy in treating cancer.
Cognitive Function
Caloric restriction and intermittent fasting have been shown to have positive effects on neuronal cells and tissue in animal models, delaying the onset and progression of neurodegenerative diseases and improving cognitive function. Animal studies suggest that caloric restriction and intermittent fasting can delay the onset and progression of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, and reduce the accumulation of harmful proteins in the brain.
To sum it all up
Calorie restrictions work through nutrient and stress-responsive metabolic signalling pathways, including TOR, AMPK, IIS/FOXO, Sirtuins, and autophagy. This improves cellular function and prevents age-related diseases.
Caloric restriction and intermittent fasting activate the sirtuin pathway, which results in the deacetylation of various proteins, including histones and transcription factors. The deacetylation of these proteins alters gene expression, resulting in changes in metabolic pathways such as TOR and IIS.
The TOR pathway regulates cell growth and proliferation, and its inhibition is linked to lifespan extension. The IIS pathway regulates glucose homeostasis and insulin signalling, and its inhibition is also linked to lifespan extension.
Both caloric restriction and intermittent fasting result in an overall reduction in caloric intake, which can also contribute to lifespan extension through a variety of mechanisms, such as reducing oxidative stress and increasing autophagy.
