September/October 2022

Intermittent Fasting
By Jennifer Lutz
Today’s Geriatric Medicine
Vol. 15 No. 5 P. 24

Should you recommend it to your geriatric patients?

Intermittent fasting: It’s considered a safe and valued tool by some practitioners and a dangerous trend by others. Proponents insist that fasting protocols can decrease inflammation, improve insulin sensitivity and cardiometabolic metrics, stave off cancer, offer neuroprotection, and slow the aging process. Critics are concerned that fasting could do more harm than good—particularly in an aging population. Amidst all the noise, recent research offers clarity. Certain forms of fasting seem to have some health benefits but should be applied on an individual basis and with a specified purpose.

The Many Forms of Fasting
Intermittent fasting has become the darling of health writers, dieting apps, and celebrity blogs, but to unpack the science, it’s necessary to specify the different forms of intermittent fasting. “Intermittent fasting is such a broad term; it can mean a million things. There are many different types of intermittent fasting; to me it’s an umbrella term,” says Stephen Anton, PhD, chief of the clinical research division at the University of Florida’s department of aging and geriatric research. While intermittent fasting is indeed a broad term, it’s generally divided into two main categories: periodic fasting (PF) and time-restricted feeding (TRF). Within these categories, there are variations, such as alternative-day fasting, and time restrictions on feeding, usually ranging from six- to 12-hour eating windows. A third approach to fasting, which has suggested clinical benefit, is the fasting mimicking diet (FMD). Before engaging in discussions about health and fasting, it’s important to understand the protocol of these three different approaches.

PF involves sustaining a period of 24 hours or more without caloric consumption. A popular PF diet is the 5:2 diet, which encourages two fasting days per week and allows for unrestricted eating during the other five days. TRF protocols strive to attain many of fasting’s benefits with a lower side effect profile. A popular TRF diet is the 8-hour diet, which involves eight hours of calorie consumption and 16 hours of fasting daily. FMDs allow only certain amounts of specific foods, and research has suggested that they’re associated with the same benefits of fasting without the potential harms. These diets are generally composed of foods low in protein and sugar and high in unsaturated fat.

To accurately understand the clinical basis for FMDs, Today’s Geriatric Medicine speaks with Valter Longo, PhD, Edna M. Jones Professor of Gerontology and Biological Sciences, director of the Longevity Institute at the University of Southern California Leonard Davis School of Gerontology in Los Angeles, and director of the Longevity and Cancer Program at the IFOM Institute of Molecular Oncology in Milan, Italy. “The protocol is generally a five-day fasting mimicking diet every three months or so, which shows clear anti-inflammatory effects. As we’ve demonstrated in clinical trials, you have a metabolic reprogramming.”

The Biological Basis for Fasting
The primary mechanism responsible for many of fasting’s benefits involves a metabolic switch.1 As glycogen reserves in the liver are depleted, lipids from stored fat (adipocytes) are metabolized to free fatty acids, which are released in the blood and metabolized by the liver to produce ketones and acetoacetate. Research has shown that this process can enhance the transcription factors responsible for mitochondrial biogenesis and improve mitochondrial functioning. These ketones are then transported into cells with high metabolic energy, such as neurons and muscle cells. Within these cells, ketones are metabolized to acetyl coenzyme A, which enters the tricarboxylic acid cycle to generate adenosine triphosphate (ATP).

The processes involved in this metabolic switch have significant effects on biological processes throughout the body. During food restriction, the body produces increased amounts of the ketone beta-hydroxybutyrate (beta-OHB), an important ligand in the activation of HCA2 (also known as GPR109A), a hydrocarboxylic acid receptor that mediates profound anti-inflammatory effects.2 β-OHB also decreases proinflammatory cytokines, endoplasmic reticulum stress, and the NLRP3 inflammasome, activating the antioxidative stress response.3,4

Other benefits conferred by this metabolic switch relate to more efficient energy production at a lower cost. “It’s like running off a super fuel for a period. More ATP is being produced, and there are less byproducts, which decreases oxidative stress in the cell,” Anton says.

Many of the benefits incurred by fasting are mediated by certain signaling pathways that regulate or affect aging and longevity. For example, adenosine monophosphate-activated protein kinase (AMPK) acts as an energy stress sensor, inhibiting acetyl-CoA carboxylase. Reduced insulin/IGF-1 signaling leads to activation of the forkhead box protein (FOXO) transcription factors. During the fasted state, mTOR signaling (which blocks tissue repair when nutrients are plentiful) is downregulated. 5 Simultaneously, human growth hormone is upregulated.

Autophagy has garnered much media attention in relation to intermittent fasting. The idea is that when the body fasts for prolonged periods of time, the cellular process of clearing out damaged or intrusive cells is heightened. While this process plays an important role in the aging process, increased autophagy is likely limited to longer fasting protocols and is a target of fasting-mimicking diets, such as ProLon, which lasts for five days.6

However, while autophagy is important, it’s unclear if increased autophagy is desirable. “Think about an area of a town that is worn out and old, and you take down a bunch of buildings, that’s autophagy,” Longo says. “So, if you went to the worst area of your town and took down 20 buildings, is that good? What we are looking for with the fasting mimicking diet is a rejuvenated profile. The important thing is that you rejuvenate, you make it healthier, you make it better, and that’s quite a sophisticated program; autophagy is maybe 10% of it.”

Metabolic flexibility is another term interlocked with fasting and is defined by the metabolism’s ability to efficiently switch between dominant energy sources. Periods of fasting and feeding are thought to improve metabolic flexibility and enhance mitochondrial health.5

Fasting and the Aging Process: Benefits Beyond Caloric Restriction
Chronic inflammation promotes disease, impairs cognitive function, and decreases the lifespan.7 Fasting has been shown to decrease inflammatory markers. Researchers at Mt. Sinai found that intermittent fasting decreases the release of proinflammatory cytokines, suggesting that intermittent fasting could be a powerful treatment for inflammatory conditions such as autoimmune and rheumatoid diseases.8 Importantly, the researchers found that while fasting decreased the release of monocytes related to chronic inflammation, it does not interfere with their role in fighting acute infection. The researchers believe that regulation of AMPK and PPARα pathways in the fasting state were primary contributors to the reduction in inflammation. The study showed that fasting also modified metabolic activity and gene expression patterns that are predictive of the improvement of chronic inflammatory and autoimmune disorders such as rheumatoid arthritis and multiple sclerosis.

Cell senescence is another target of fasting protocols and plays an important role in the aging process. Many of the energy sensors involved in fasting/feeding are closely related to aging and longevity, such as AMPK, a central regulator of energy homeostasis that has also been indicated in decreased oxidative stress and the regulation of metabolic diseases. Pharmacologic approaches to AMPK activation (such as metformin) have been shown to reduce age-related changes in liver sinusoidal endothelial cells as well as increases in ATP, cyclic guanosine monophosphate, and mitochondrial activity. Resveratrol has also been researched for its role in decreasing cellular senescence via the AMPK/FOXO pathway. Using human cell cultures, researchers have shown that resveratrol activates AMPK/FOXO3 signaling, thereby guarding against oxidative stress-induced senescence and proliferative impairment.9 The activation of the AMPK/FOXO pathway during the fasting state activates the same pathways and could play a significant role in longevity.5

Additionally, the Sirtuin pathway (also activated in the fasted state) has been shown to suppress cellular senescence.10 This is primarily accomplished by delaying age-related telomere attrition, sustaining genome integrity, and promoting DNA repair.9

Oxidative stress is another hallmark of aging. Fasting protocols have been shown to decrease oxidative stress on a short-term and long-term basis. Intermittent fasting protocols, such as alternate day fasting, have been shown to decrease oxidative stress and reduce the activation of reactive oxygen species.10 Recent research on metabolites suggests that fasting may also decrease oxidative stress via the metabolites that are upregulated during the fasted state. In a small study that observed four healthy individuals during a 52-hour fast, researchers observed an increase in several antioxidants.10

Insulin sensitivity plays an important role in healthy aging and in the prevention of diseases such as diabetes, cardiovascular disease, and fatty liver disease. Intermittent fasting protocols have been shown to decrease fasting glucose and fasting insulin and reduce insulin resistance. 11 In addition to promoting positive effects during the fasted states, these protocols have been shown to increase insulin sensitivity after refeeding. FMDs, in particular, have shown promise in their ability to potentially reverse insulin insensitivity.6

Diabetes affects approximately 26.8% of adults aged 65 and older.12 In mice models and in studies on human pancreatic cells, FMDs have been shown to reduce the symptoms of type 1 and type 2 diabetes. 13 The study showed that periods of FMD and refeeding promote the growth of new insulin-producing pancreatic cells.

Cardiovascular disease remains the leading cause of death globally.14 Many of the risk factors for cardiovascular disease, such as high blood pressure and cholesterol, can be mediated through diet. The ketogenic state, induced by intermittent fasting, has been linked to decreases in cardiovascular risk factors. In clinical trial, intermittent fasting has been shown to decrease blood pressure and improve lipid profiles.15 In one trial, researchers followed 100 “generally healthy participants” to test the effects of a FMD on cardiovascular health. The diet positively influenced body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and LDL cholesterol, and C-reactive protein, although results were more significant in participants at risk for disease.16

Cancer cells may be particularly sensitive to fasting protocols. Research suggests that intermittent fasting can change the energy metabolism of tumor cells, inhibiting growth and improving antitumor immune response.17 Intermittent fasting may also increase the success of chemotherapy and radiotherapy, while reducing side effects. The inhibition of tumor cell growth is attributed to the inhibition of IGF-1/AKT and mTORC1 pathways with the simultaneous activation of AMPK via the SIRT1 and SIRT3 pathways. Additionally, FOX3 reduces the level of reactive oxygen species.17 Fasting also has been shown to increase tumor cell apoptosis. Regarding FMDs, a first-in-human clinical trial showed positive results. The five-day FMD was used in combination with standard-of-care antitumor therapies and completed in cycles. Key findings included the downregulation of immunosuppressive myeloid cells, which occurred independently of concomitant antitumor therapies, as well as an increase in activated CD8+ T cells and natural killer cells. The researchers also found that FMD led to relieved immune suppression and enhanced T-cell activation.

Neurodegeneration is one of the greatest age-related health concerns. In animal models, fasting has been shown to ameliorate cognitive impairment and protect neurons.18 The mechanism by which fasting protects neurons from degeneration has been linked to the increased expression of neurotrophic factors, including BDNF.19 The ketone body βOHB and mitochondrial sirtuin SIRT3 have also been shown to play an important role.6 The upregulation of these factors, which has been observed in intermittent fasting (and are significantly more pronounced in FMD) may delay the onset of Alzheimer’s disease.6

Stem-cell self-renewal is a powerful mechanism for longevity and has been linked to fasting and refeeding protocols.6 Stem-cell regeneration is stimulated in both intermittent fasting and FMD through nutrient-sensing pathways.20,21 In animal models, cycles of FMD have also been shown to promote the proliferation of stem and progenitor cells by reverting the age-related decline in mesenchymal stem and progenitor cells.22

Fasting and the Aging Process: Potential Harms and Contraindications
Although the benefits of fasting protocols are many, they don’t come without risk. Longo explains that we still need more clinical trials, noting there “are pluses and minuses; it can be beneficial for certain things and detrimental for others. We focused on the fasting mimicking diet because I searched for many years for something that could be as beneficial as chronic calorie restriction without the problems.” Those potential problems include an increased risk of gallstones in females,6 decreased testosterone levels in resistance-trained males,23 and a downregulation of the hypothalamuspituitary-thyroid axis.24

The risk for gallstones seems to be associated with water-only fasts and is caused by decreased gallbladder movement.25 FMDs seem to eliminate this problem, as does a protocol such as the 5:2 diet, which includes 25% calorie intake during “fasting” days. The frequency which with a person fasts can also have an impact. “If someone says they are going to fast once a month at 25% of their daily calories, I think there’s a very high chance that it could be useful and a very low chance that it would be harmful, (even with a one-day water fast),” Longo says, but he also cautions, “That’s probably; it’s not a clinical trial.”

The decrease in testosterone levels was reported by a small study that specifically examined the effect of intermittent fasting on 34 males undergoing resistance training. After eight weeks on an intermittent fasting protocol, there was a reduction in testosterone; however, this did not correlate with a reduction in muscle mass or strength. Testosterone levels were tested after the eight-week period with no follow-up to measure baseline hormone levels after participants returned to a standard eating schedule.23

For individuals with healthy thyroid functioning, fasting protocols are unlikely to cause significant changes. A study on Ramadan fasting (which entails a 30-day period of fasting from sunrise to sundown) in healthy girls aged 9 to 13 showed a significant decrease in triiodothyronine (T3) during fasting; however, these levels remained within normal range.26 At the same time, rodent models show increased local T3 concentrations in the hypothalamus during food deprivation as well as a downregulation of the hypothalamus-pituitary-thyroid axis and decreased serum thyroid hormones concentrations.24 Another study specifically examined the effect of Ramadan fasting on thyroid function in hypothyroid patients on thyroxine replacement therapy.27 The study showed adverse changes in thyroid functioning, which resolved within two to three months after Ramadan. Studies regarding fasting and thyroid function are scarce. When considering Ramadan studies, interference with the timing of medication must also be considered. Regardless, fasting does influence thyroid regulation and should be taken into consideration.

Finally, fasting may pose a risk for older populations if nutrition needs are not met. Generally, Longo says, “fasting is not recommended for people younger than 18, older than 70, or pregnant.” A doctor should be involved, he adds, for patients with cardiovascular disease or diabetes. “The biggest enemy of fasting and fasting mimicking diets are drugs affecting glucose, like insulin, and drugs affecting blood pressure.” At the same time, when used as a treatment, FMD could be beneficial in an older population. “We’re doing a clinical trial right now with Alzheimer’s patients—they are all almost 70. I think if a fasting mimicking diet is used for a specific reason, it can be more beneficial than harmful,” Longo says. At the same time, he cautions that the diet is still experimental, and he doesn’t recommend it in place of first-line treatments—particularly in high-risk patients. However, when patients aren’t responding to traditional therapies, it may be suggested. “If the patient is not responding, for example, if a cancer patient’s chemo isn’t working and it’s causing lots of side effects, a fasting mimicking diet may be recommended.”

Fasting can have many benefits in the aging process but should be used responsibly. Based on the potential side effects of fasting, factors to monitor would include digestive issues, nutrition, and hormonal fluctuations, among others.

Fasting: Final Verdicts and Clinical Applications
Fasting isn’t one size fits all. When used to incur specific results, fasting is shown to be a useful practice but it could have negative impacts when used too frequently or for extended durations. The biological mechanisms that are activated during fasting are also variable based on certain factors. According to Anton, “What we’re talking about is switching to using ketones in addition to using glucose as a source of energy. The level of ketones gradually increases as the fasting period continues but is also dependent on what you do during the fasting period. So it’s not just a matter of time.” Anton also explains that what one eats and does before the fasting state will influence the body’s reaction. Additionally, a person’s personal metabolic profile will have an impact.

Choosing a specific type of fasting protocol will depend on individual needs and preferences. TRF may be easier to adhere to than PF with similar benefits. It’s not a perfect science; while a person may get optimal results from a daily eight-hour diet, practicing intermittent fasting two to three days a week will likely offer some benefits. And while intermittent fasting is generally safer than extended water fasts, it may be best used for short durations, such as for one- or two-month periods. Longo cautions against using intermittent fasting for durations longer than two months due to potential side effects but recognizes its benefits. FMDs have been shown to have robust long-term results without the same risk profile as water-only fasting but may be too costly for some. Longo recommends FMDs to be used three times a year for the average person and four to six times a year when managing a disease such as obesity.

Regarding a daily eating regimen, Longo believes a 12-hour fast offers benefits without risk, saying that “It’s about as good as it gets.”

Fasting isn’t exactly available in pill form, but as clinical trials increase in prevalence, a recommendation to use fasting protocols may meet the criteria for a prescription.

— Jennifer Lutz is a freelance journalist who covers health, politics, and travel. She’s written for both consumer and professional medical magazines as well as popular newspapers. Her writing can be found in Practical Pain Management, Endocrine Web, Psycom Pro, The Guardian, New York Daily News, Thrive Global, BuzzFeed, and The Local Spain. In addition to journalism, Lutz works as a strategies and communication consultant for nonprofits focused on improving community health.

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