In Silicon Valley, the hub of anti-aging research and funding, countless entrepreneurs and high-profile celebrities use intermittent fasting to combat the effects of aging. Within these communities, studies are often cited without a firm understanding of the scientific mechanisms that modulate them.
In How to Fast we provided a brief introduction to fasting and why it is a compelling practice for the Neurohacker Collective team and community alike. We answered the question “what’s fasting,” with an emphasis on how scientific research defines different types of fasting regimens (e.g., calorie restriction vs fasting).
In What to Expect While Intermittent Fasting we shifted gears a bit and focused on subsets of fasting behaviors that are being practiced by biohackers. We systematically explained the different ways to begin fasting and the modern application by members of the community, with an emphasis on “how to fast” by using fasting behaviors such as time-restricted eating and intermittent fasting.
In this article, we are going to explore the mechanisms that create the fasting benefits for anti-aging and longevity. While this part is a bit more scientific than the others, we will emphasize crucial components in a digestible format.
This will provide a deeper understanding of the benefits of intermittent fasting, but also introduce basic vocabulary and concepts related to healthy aging.
Fasting Diets: Micro-Fast vs Multi-Day Fasting
Before we dive into the mechanisms of fasting, as they relate to healthy aging, it’s valuable to address the differences between micro and multi-day fasting. Recognizing that there are differences between the fasting methods we covered in What to Expect While Intermittent Fasting provides us with context to go deeper into the science.
The short-term fasting protocols, which include the subtype of intermittent fasting called time-restricted eating, where no calories are consumed for a period of between 16 - 20 hours, have many independent benefits.
These micro-fasts can support metabolic health by improving glycemic control, lowering insulin levels, and controlling body weight.1 This suggests short-term fasting for weight loss may be a credible lifestyle choice. According to some human studies, fat mass can go down while physical strength remains unchanged2 (an often cited fear of bodybuilders and athletes alike).
Other fasting benefits include cardiovascular support, increased brain-derived neurotrophic factor (BDNF) signaling in the brain,3 and evidence that nightly fasting for more than 13 hours supports a lower risk of cancer recurrence.4
Prolonged fasting (PF) regimens (lasting over 48 hours) stimulate different physiological changes that confer unique fasting benefits, which fall into functional areas such as immune strength, longevity, and healthy aging.
A small piece from a 2014 study in Cell articulates the difference between micro and prolonged multi-day fasting:
“The physiological changes caused by PF are much more pronounced than those caused by caloric restriction or fasting lasting 24 hours or less in part because of the requirement to fully switch to a fat- and ketone bodies-based catabolism after glycogen reserves are depleted during PF.”5
The study found that prolonged fasting increased white blood cells (a biomarker for immune health) and was a useful adjunct therapy alongside chemotherapy for killing cancer cells in animals. One rationale behind this finding is that cancer cells thrive and grow on glucose, so prolonged fasts act to starve cancer cells and support anti-cancer immune efforts.
The mechanisms of multi-day fasting that support healthy aging are the topics of the following sections.
Anti-Aging Benefits of Calorie Restriction
Of all the interventions that combat aging, calorie restriction (CR) is the most efficient. As we described in part 1 and 2, traditional CR reduces calories by 20 - 40% for extended periods, which is neither recommended for performance nor popular among biohackers due to the mental distraction.
The CR research in humans and animals has elucidated many of the mechanisms involved in aging that were previously unknown. Calorie restriction supports five main mechanisms underlying healthy aging as per a well-written and organized paper in Clinical Interventions of Aging entitled Does eating less make you live longer and better? An update on calorie restriction:
Note: This daunting assortment of scientific acronyms may seem challenging, but we will break them down as simply as possible.
- Cell Proliferation: IGF-1 and TOR (specifically mTOR)
- Inflammation: NF-kB
- Mitochondrial physiology: AMPK / SIRT
- Autophagy: FoxO
- Antioxidants: Nrf2
It’s worth noting that all of these mechanisms are interrelated. Humans (and aging) are complex systems. For example, while downregulation of mTOR was categorized in the article under Cell Proliferation, this mechanism is also involved with autophagy.
Figure: Mechanisms of Aging Impacted by Calorie Restriction
One group called the Calorie Restriction Society have imposed a CR regimen on themselves consuming ~ 30% fewer calories for an average of 15 years. As they mention in the Clinical Interventions of Aging article this CRON community (caloric restriction with optimal nutrition) provides some long-term human validation, but full “...CRON data on longevity and mortality are not yet available.” Until this data is complete, we’ll focus on the underlying mechanisms.
Cell Proliferation (aka: Growth Balance)
For our purposes, the term cell proliferation (as used in the article linked above) refers to the tendency of the human system to be in an anabolic state (building up) with the presence of calories. When there is caloric abundance (which is common in modern, industrialized countries) cells are consistently in an anabolic state.
The act of caloric restriction can shift the balance in the system by stimulating catabolic (breaking down) pathways. Two pathways are particularly important including insulin-like growth-factor-1 (IGF-1) and mammalian target of rapamycin (mTOR).
IGF-1 and mTOR are nutrient sensors. They regulate cellular resources depending on the availability of calories. During a fast, fewer calories leads to IGF-1 and mTOR downregulation, which signals for the cells and organelles to be recycled and repurposed.
The Clinical Interventions of Aging paper notes that “Reduced mTOR signaling has been demonstrated to extend lifespan in different organisms. The mTOR inhibition has been largely identified as a longevity assurance mechanism, and the availability of rapamycin and other mTOR inhibitors makes this pathway a valuable target for interventions to extend healthspan.”
mTOR is specifically a protein sensor according to Dr. Jason Fung. In this 4 minute video, he explains how eating only fat (and no protein) could theoretically modulate mTOR positively. This is one of the reasons I sometimes consume a low-dose fat-based drink called Nectar during a micro-fast.
Benefits of Fasting for Inflammation
As humans age, damage accumulates throughout the body (more on that later). This damage is recognized by immune receptors, which stimulate the production of numerous proinflammatory molecules. In the worst instances, accumulated damage is so great that inflammation becomes chronic (continuous), which accompanies numerous age-related diseases (and may be contributing to them).
Inflammation is in itself not bad per se (acute inflammation is part of healing), but there is evidence that chronic inflammation (also called “age-associated inflammation” or “inflammaging”) can be heavily correlated with poor health biomarkers. Among other mechanisms, calorie restriction inhibits nuclear factor-kB (NF-kB), which exerts an anti-inflammatory effect. NF-kB is thought of as a “master regulator of inflammation,” so reducing its activity downregulates many parts of proinflammatory signaling.
Animal models suggest this anti-inflammatory effect can have cognitive enhancing properties. One study considered fasting a form of “eustress” (beneficial form of stress) versus “distress” (the negative stressors of life that accelerate aging). They concluded “...[intermittent fasting (IF)] caused a remarkable reduction of the plasma inflammatory factors… In conclusion, IF could improve cognitive function and preserve the brain against distress by regulation of inflammatory response pathway.”6
One of the main reasons I engage in multi-day fasting is to achieve levels of beneficial stress for both my physiology (as described above), but also my psychology. I value the grit and confidence that grows from voluntarily creating challenges for myself.
How Fasting Supports Mitochondrial Physiology
The mitochondria are organelles within cells. They are integral for producing ATP (cellular energy) so that cells may do more work. This work can be translated into physical labor, as is in the case with muscle cells, or cognitive tasks, as in the case with brain cells.
Aging impairs the overall quality of the mitochondrial network, decreasing the destruction of damaged/dysfunction mitochondria (mitophagy) and the generation of new mitochondria (mitochondrial biogenesis). Calorie restriction supports both of these processes, resulting in a higher quality mitochondrial network.
The two pathways most commonly associated with mitochondrial support are AMP-dependent kinase (AMPK) and sirtuins (SIRT genes). Both of these pathways are sensitive to shifts in the NAD+ / NADH ratio. Calorie restriction increases NAD+ accumulation, which activates AMPK and sirtuins. The Journal of Cell Science concludes that “the fact that sirtuins require NAD for their enzymatic activity connects metabolism to aging and aging-related diseases.”7
The importance of NAD+ / NADH to the AMPK and sirtuins pathways is one reason why oral supplementation of their precursors has grown in popularity (nicotinamide riboside use has become common among biohackers, but all niacins boost NAD+).
Both AMPK and sirtuins are integral in mitochondrial biogenesis and the process of mitophagy (mitochondrial recycling and removing of dysfunctional organelles that comes with age), so help with maintaining a “younger” mitochondrial network.
When cells are scarce of glucose (as they would be during an extended fast or following intense exercise), ATP production drops (at least initially). AMPK senses the decrease in ATP and reduces energy utilization while upregulating many processes that act to replenish ATP. The result is that cells (and mitochondria) are better able to make ATP in the future. Calorie restriction activates the AMPK pathway in many tissues in animal models, but whether this mechanisms is involved in humans during caloric restriction is unstudied.
Sirtuins also have a crucial role in aging as a sensor for biological stress. When scientists manipulate and increase the expression of sirtuins in yeast, this alone promotes longevity.8 In contrast, according to Harvard researcher David Sinclair, “if you knock out SIRT2, you don’t get the benefits of calorie restriction.”9
For a more in depth exploration of sirtuins and their effects on aging, we recommend Dr. Peter Attia’s podcast with Dr. David Sinclair.
What is Autophagy?
The term autophagy literally means “self-eating”, which is a good characterization of the autophagic process.
During autophagy, cleaning mechanisms remove old cell membranes, organelles, and other “cellular junk” that has accumulated over time and may impede optimal cellular (and mitochondrial) performance. While old, broken parts of our cells are being removed, growth hormone—a hormone that’s amplified during fasting—signals the body to produce new replacements. The result of autophagy is essentially a recycling and renovating process for our cells.
mTOR (discussed above) induces activation of forkhead box (FoxO) proteins. Autophagy and mitophagy are “FoxO-dependent,” suggesting this transcriptional (i.e., signaling) molecule is the integral component of these processes.
How Fasting Supports Anti-Oxidant Defenses
As humans age, reactive oxygen species (ROS) generally increase as our natural antioxidant defenses decrease. This imbalance becomes greater over time, as damage accumulates and mitochondrial dysfunction becomes more prevalent.
Normal production of oxidants in specific cell-types is useful to regulate pathways (ROS are involved in some signaling processes), so finding the right balance as we age is valuable. This right balance might be critical for optimizing mitochondrial performance and is sometimes referred to as mitohormesis, the idea being we need a “just right” amount of ROS, with too little resulting in subpar performance but high amounts causing damage. This is particularly important for tissues that depend on producing large amounts of ATP for their metabolism (including muscle, brain, and heart).
One of the understandings that have come from mitohormesis is that we need some amount of ROS to trigger adaptive responses that upregulate antioxidant defenses and make cells and mitochondria better to be able to deal with stress and toxins. Fasting can help promote anti-oxidant defenses. Calorie restriction activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which is a “regulator of cellular resistance to oxidants.”10 This protein supports antioxidant defenses through the following:
- Regeneration of oxidized cofactors and proteins (re-growing more of the old “good stuff”)
- Catabolism of superoxide and peroxides (getting rid of the “bad stuff”)
- Synthesis of reducing factors (creating new “good stuff”)
- Increase of redox transport (increasing efficiency of existing machinery)
Nrf2 is not the only mechanisms that promote antioxidant defenses and support. As with all the five mechanisms that we’ve broken down, they are interrelated and support each other across the complex human system.
Fasting for Healthspan & Lifespan
The amount of time we live is called lifespan. The length of time that a person is healthy and functional—not just alive—is called healthspan.
Calorie restriction (including intermittent fasting, time-restricted eating, and prolonged fasting) is valuable for effecting both lifespan (in studied organisms but not yet proven in humans) and the healthspan (in organisms including humans).
It is common within the aging and longevity space (at least via media depictions) to focus on lifespan to the detriment of quality of life.
In contrast, the length of time that a person is healthy and functional is correlated with higher quality of life. Healthspan can be mediated by dietary interventions, exercise as an example, but also social interaction, community, and family. A study from Innovations in Aging followed 5,000 Japanese participants for over 20 years and concluded “...social interaction is positively related to longevity and life satisfaction.”11 Healthspan may be more valuable to emphasize than lifespan alone.
Programmed Aging vs Damage Accumulation
Within the aging community, there is a debate between the importance of programmed aging vs damage accumulation. As with most physiological debates, humans are complex systems that probably involve a combination of both.
Programmed aging refers to the changes in how our genes are expressed as we age. Some are overexpressed and others are underexpressed.
Damage accumulation is characterized by cellular and mitochondrial damage over time.
Both programmed aging and damage accumulation occur at the cellular level with each amplifying the effects of the other (i.e., changes in gene expression accelerate damage accumulation, while damage accumulation affects a cell’s ability to have healthy gene expression).
Aging Benefits of Intermittent Fasting
This scientific overview of the mechanisms involved with aging and longevity is valuable beyond the context of fasting. As you will see in part 4, these mechanisms inform nootropics and other techniques we can use to support healthy aging.
Even though we have outlined many benefits that arise when we induce some degree of temporary “starvation,” it’s worth noting that there’s more than one way to trigger some of these responses (see part 2). It’s also important to understand that some of the benefits occur during the fasting period, but others occur when we start eating normally again.
A recurring theme from the American Academy of Anti-Aging Medicine (A4M) conference that was held mid-December 2018 was the reminder that starvation (i.e., fasting) primes the system for rejuvenation, but it is the refeeding that rebuilds the new cells and organelles to increase health. Masochistic semi-starvation because it is “good” may be folly when cycles of moderate fasting interventions will do.
If you feel more convinced that fasting benefits are worthwhile to explore, go back to read part 2 for fasting implementation strategies. In part 4 we’ll answer common questions and help make fasting as practical and sustainable as possible.
For more information on the topic, see our related podcasts:
9 Listen ~ 26:00 minutes into the podcast. https://peterattiamd.com/davidsinclair/