Can Fasting Increase Longevity?

Background Context

Life expectancy has continually increased with advances in healthcare and economic prosperity. However, many diseases have increased in prevlance, in part due to treatments that can now extend life for those with the disease. However, talk about delaying or “treating” ageing (or ‘aging’ in North America) should consider how we could shorten the time of morbidity, or increase the healthspan. To do this we need interventions that can delay the physiological change that results in disease and disability.

One propsed intervention that has garnered a lot of excitement, owing to some interesting research, is the potential use of fasting to increase longevity and/or healthspan. Within this broad category, various different dietary interventions have been suggested, including various forms of intermittent fasting, time-restricted eating, dietary restriction of certain nutritients, calorie restriction or a “fasting-mimicking” diet.

But what does the current evidence tell us? Do the conclusions match the excitement? Which claims are grounded in solid science and which ones are pseudoscientific extrapolations?

Aiming to Increase Longevity & Healthspan

Life expectancy continues to increase in most high-income societies and over the past century, life expectancy has increased by more than two years per decade. This is largely due to advances in healthcare.

And in the last decade this can be largely attributed to advances in the upper end of health distribution. Recent population-based findings show that life expectancy has increased faster in subpopulations with a history of disease, compared to the general population. Whilst the evidence is from the Swedish population (i.e. a country with high-quality, universal healthcare coverage), improvements in life expectancy were observed regardless of comorbidities or educational attainment.

It is likely that increases in life expectancy at older ages will continue, but life expectancy at birth is unlikely to reach levels above 95, unless there is a change in our ability to delay the ageing process.

Whilst we are living longer, the prevalence of disease has increased, largely due to treatments that extend life for those with disease. Given that the age of onset of most health problems has not markedly increased, it is still unclear if morbidity is actually reducing. Some reductions in the prevalence of physical disability and dementia have been reported, and large ageing studies have shown greater longevity resulted in fewer, not more years of disability.

And really the goal of any longevity or ‘anti-ageing’ intervention, should be to reduce morbidity and increase healthspan, rather than simple aim to extend years of life. Shortening time of morbidity or increasing the healthspan requires new strategies that could delay or “treat” ageing or delay the physiological change that results in disease and disability.

Emphasis on evidence-based, preventative lifestyle strategies are becoming increasingly important in the quest of achieving the oldest of age. Several modifiable lifestyle factors have been identified that may preserve cognitive and physical health into old age. These include:

• Maintaining good cardiovascular health
• Engaging in regular physical activity
• Low alcohol intake
• Not using tobacco products
• Consuming a healthy dietary pattern

What is Ageing?

There is no singular definition of ‘ageing’ as it can be considered in multiple ways (i.e., behavioural, physiological, cellular etc.). Biological ageing is generally defined as “a series phenomenon of functional, structural, and biochemical changes that occur throughout cells and organs, disrupting homeostasis in the body and ultimately leading to death”. A definition of ‘successful ageing’ is a little less clear. It is likely multidimensional and person-centric.

With advancing age, even in the absence of disease, all physiological systems decline in both capacity and function. The rate of decline is dependent on many factors, including:

• Genetics
• Environment
• Lifestyle

In 2018, the Office of National Statistics reported dementia to be the leading cause of death in older adults in England, overtaking cardiovascular disease, stroke, and lung cancer. Similar trends have been expressed globally, which are largely driven by the increasing older adult population, longer life expectancies and improved diagnostic procedures.

Aside from age-related declines in cognitive function, with advancing age adults will also experience:

• a reduction in overall muscle mass and strength
• immune dysfunction
• increased risk of certain cancers

In the absence of curative treatments for some age-related diseases, the focus on reducing the risk and/or delaying the onset is a key priority for all public health authorities and governments.

Emerging research highlights newer potential dietary and nutritional factors, for example caloric restriction (CR). Fasting has also been explored as a potential approach that could support longevity, i.e., the capability to survive past the average age of death.

More importantly, over the last decade, researchers have focused on exploring the benefits of fasting in terms of extending healthspan; the years a person is in good health, not just the number of years of life. This has led to an increase in research targeted at treating ageing.

In this Statement we will focus on fasting and examine whether it could benefit longevity. Specifically, the question is:

Can fasting increase lifespan AND maintain (or increase) healthspan while doing so?

What Happens When We Fast?

Dietary Restriction & Types of Fasting Interventions

Dietary restriction (DR) may take the form of either:

1. Caloric restriction (CR): a chronic reduction of average daily calorie intake (typically 20-40% below normal)
   
2. Nutrient restriction (NR): the reduction in specific components of the diet such as protein or certain amino acids.

It has been suggested that DR, if employed to a level that does not compromise overall health or lead to deprivation of essential nutrients, could be one of the most encouraging modifiable strategies to extend lifespan in humans. Although it is a simple concept, the habitual reduction of calories or food intake is more difficult to practice for most people.

Recently, various fasting approaches have been proposed as alternatives to outright caloric restriction, including:

• Intermittent fasting (IF): Commonly in studies this takes the form of two “fasting” days per week, where calorie intake is kept to around 500–700 kcal, with the five other days being “normal” eating.
  
• Time-restricted feeding (TRF) or Time-restricted eating (TRE): Food intake is restricted to a compressed feeding window each day, usally of around 6–12 hours in duration.
  
• Fasting mimicking diet (FMD): 30–50% of normal caloric intake for 4–7 consecutive days, followed by a refeeding ad libitum period (typically repeated monthly).

The periodic nature of fasting is likely to avoid the constant hunger that can be experienced with CR regimens, and therefore compliance with the regimen may be greater. More recently researchers have explored the much less severe fasting strategy, the fasting mimicking diet, developed and investigated by Professor Valter Longo and his group at the University of Southern California. This evidence will be discussed in more detail later in this statement.

Most investigations have employed various strategies, the use of strategies like IF or periodic fasting, need to be limited or merged and replaced by standardised terminology to clearly define interventions that can be implemented in clinical studies and eventually through general instruction.

In a 2021 review published in Nature, Longo et al. described the metabolic effects of fasting on ageing in detail. The general premise is that fasting regimens may trigger a metabolic shift from glucose-based to ketone-based energy, with increased stress resistance, cell survival resulting in decreased incidence of disease and increased longevity. This is usually coupled with weight loss, which also likely attributes to the benefits of fasting.

Physiological Adaptations in Response to Fasting

Fasting regimens, such as IF, are understood to play a role in cell protection and repair, as well as removal of impaired cells. This is in part through the fluctuations in nutrient levels, which are detected by nutrient-sensing pathways. This is a key difference to standard caloric restriciton or nutrient restriction regimens, which are instead largely focused on the potential benefits of constant caloric or macronutrient restriction.

Fasts of 10-14 hours or more, result in:

1. Depletion of liver glycogen stores and the breakdown of triglycerides to free fatty acids (FFAs) and glycerol in adipocytes (fat cells).
2. FFAs released into the circulation are transported into hepatocytes (liver cells), where they produce the ketone bodies.
3. FFAs also activate important transcription factors, resulting in the production and release of fibroblast growth factor 21, a protein with effects on cells throughout the body and brain.
4. Selective transcription factors are transported into cells where they can be metabolized to acetyl CoA, which enters the tricarboxylic acid (TCA) cycle and generates ATP.
5. Reduced levels of glucose and amino acids during fasting result in reduced activity of the mTOR pathway and up-regulation of autophagy.

Other impacts of prolonged fasting (48–120 hours) have been considered. It has been shown that extended fasts in mice lead to acute decreases in immune cells, however they are restored upon refeeding. This is suggested as an advantage; i.e. the cycles of prolonged fasting and re-feeding promote stem cell self-renewal to reverse immunosuppression. However, implications for humans are difficult to know, owing to the complexity of the immune system and the need for more research.

Effects of Fasting on Healthspan & Ageing

It has been shown that most organs respond to IF in ways that enable them to withstand or overcome the challenge of fasting and then restore homeostasis. Repeated periods of fasting have demonstrated long standing adaptive responses, such as:

• DNA repair
• Antioxidant effects
• Suppression of inflammation

The effect varies and may depend on various factors including sex, diet, and genetics.

A meta-analysis conducted by Swindell (2012) evaluating all laboratory evidence for DR from 1934-2012, reported an increase in lifespan by 14-45% in rats but only 4-27% in mice. For a standard laboratory-bred rat, with an average lifespan of 3 years, this translates to an extra 0.4 – 1.4 years of life. There is a distinct null effect of DR in some inbred mouse strains, highlighting a need for diverse animal strains and a broad genotype for wide demonstration in ageing research. Studies in monkeys have reported conflicting findings also, for similar reasons, as discussed below.

Experimental Models in Animals

Extension of lifespan and healthspan have been demonstrated in many non-human models, including yeast, mice, and monkeys. Fontana et al. cover much of the evidence in detail in their 2010 review, which considers the role of nutrient-sensing signalling pathways in mediating the beneficial effects of DR in increasing lifespan and reducing age-related disease. The authors conclude that a healthy lifespan is under the influence of multiple nutrient pathways, not a single pathway.

In general, the factors that are proposed to potentially to affect lifespan as a result of CR or DR are those associated with nutrient sensing pathways like insulin-like growth factor-1 (IGF-1) and insulin, including:

• Phosphoinositide 3-kinase (PI3K)
• Mammalian target of rapamycin complex 1 (mTORC1)
• Protein-kinase A (PKA)
• AMP-activated protein kinase (AMPK)
• Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)
• Sirtuins
• Forkhead transcription factors (FOXOs)

The scope of the review by Fontana et al. does not incorporate evidence for sirtuins, a family of signalling proteins involved in metabolic regulation, which is described in more detail by Buar et al., (2010). The interest in sirtuins increased after data was reported on their role in longevity regulation in organisms such as yeast, worms, and flies. However, controversy remains in relation to their function in ageing, as reported by Barnett et al., who found that DR increased lifespan independent of sirtuins.

Some of the earliest experimental evidence was conducted by Weindruch and Walford (1982), who published evidence for the beneficial effects of DR on lifespan and cancer incidence in middle-aged mice. The authors reported that mice, following a nutrient-enriched restricted diet, averaged 10-20% increases in mean survival times compared to control mice, and a reduced incidence of spontaneous lymphoma compared to controls.

The impact of CR has also been examined in primates, specifically rhesus monkeys, with two studies run almost in parallel starting in 1987. A 20-year longitudinal study by Coleman et al., at the University of Wisconsin demonstrated delayed disease onset and mortality. The study showed that moderate CR (30% deficit vs. control) reduced the incidence of age-related death at the time of reporting (at follow-up, 80% of CR animals survived, compared to 50% of controls). In addition, they observed a delay in the onset of age-related diseases, such as, diabetes, cancer, cardiovascular disease and neurodegeneration. However, 23-year study by Mattison et al., conducted at the National Institute of Aging (NIA), reported some improvements in overall health but not in the lifespan of the monkeys. Comparison between the two studies is challenging as there were considerable differences in a number of aspects of the studies, including differing dietary intakes, sex and environmental factors (discussed here).

Others have demonstrated evidence in mice for the potential of a Fasting Mimicking Diet to have a benefit in cancer treatment; specifically that the FMD may help healthy cells, but not cancer cells, to have an increased resistance to chemotherapy, whilst also promoting regeneration of new tissue.

Cheng et al., 2014 demonstrated that mice given an FMD regimen become protected after 6 cycles of chemotherapy and FMD. It appears that the FMD strategies, starting at middle age, reverse the effect of ageing on white blood cell numbers. Furthermore, during middle age, a twice-monthly FMD (i.e. 2 x 4-days of FMD per month) returned WBC numbers back to levels seen in youth. Furthermore, Cheng et al., demonstrated that mice following the regimen have 50% less tumours later in life and they are more likely to be benign in nature. The same laboratory provided evidence in 2016 to show that a FMD alone or in combination with chemotherapy is as effective as short-term starvation in reducing tumour progression in mice.

In a study published in Nature, Caffa et al. (2020) reported that, in mouse models, anti-cancer therapy for hormone receptor positive (HR+) breast cancer was improved by implementation of periodic fasting/FMD. The clinical translation of fasting in oncology is gaining momentum and doesn’t seem far from being prescribed as an adjunct therapy in cancer treatment, in combination with chemotherapy in future management of disease. However, it should be stressed that there is signficant nuance here, not least including the context of the specific cancer type and other important details.

Clinical Investigations in Humans

Studies in mice and non-human primates show consistent effects of CR on the healthspan, however the magnitude of the effect on life-span extension in humans is variable. At present, there are no effective treatments for some age-related or neurodegenerative diseases, such as Alzheimer’s disease and dementia, and so there has been some hope that perhaps fasting could serve as a beneficial preventative strategy for preservation of cognitive health.

Clinical studies in older adults have reported that CR can lead to improved memory, and that intentional weight loss (via CR) in overweight adults with mild cognitive impairment (MCI) lead to improved memory, executive function and global cognition.

There is a need for controlled trials of IF in persons at risk of neurodegenerative disease, or at early stages of disease, who are followed up for a long period of time. Two observational studies have examined fasting and major adverse clinical outcomes in humans. These epidemiologic studies of fasting were not based on CR but on reduced tobacco use…

The first of these studies (Horne et al., 2008) examined members of the Church of Jesus Christ of Latter-Day Saints (LDS), or Mormons. LDS members do not smoke, and the study wanted to asses whether their low coronary artery disease (CAD) risk was attibutable to the exclusion of smoking or not. The study found that LDSs had a lower risk of CAD than those of other religious preferences (adjusted OR: 0.81; 95% CI: 0.69, 0.95; P = 0.009), despite adjustment for smoking. To better understand the low CAD risk, fasting history was evaluated among 448 cardiac patients of unrestricted religious preference. Patients who reported routine fasting had lower odds of CAD (adjusted OR: 0.46; 95% CI: 0.27, 0.81; P = 0.007) than did those who did not fast. Those of religious preferences other than LDSs who reported routine fasting also benefited. A secondary finding also suggested a lower risk of diabetes.

A second observational study by the same group confirmed, and expanded on, the fasting associations with CAD and diabetes. Using the same fasting survey, a study was conducted among 200 patients (a new set of cardiac patients for the primary outcome of diabetes). The study found that patients who fasted routinely had lower diabetes risk (adjusted OR: 0.40; 95% CI: 0.16, 0.99; P = 0.044) and confirmed the first study’s findings for CAD risk (adjusted OR: 0.37; 95% CI: 0.18, 0.88; P = 0.019). In addition, ‘fasters’ had lower glucose concentrations and BMI.

Similar evidence for changes in BMI and fasting-like behaviours (overnight fasting of 18 – 19 hours and no snacking) were observed in the Adventist Health Study 2. Participants who consumed on average 1-2 meals per day (and typically more intake earlier in the day), experienced a reduction in BMI after 1 year compared to those who ate 3 meals per day. In addition, those who consumed 3 meals per day and frequently snacked, had an increased BMI. However, this marked difference was considerably impacted by age, with those older than 60 years (compared to younger participants) being more likely to experience weight loss, which could be attributed to metabolic changes seen with ageing.

The CALERIE study, a multi-centre RCT conducted in the USA, reported that a 11.9% reduction in daily calorie intake (as assessed by 7-day food records), for a sustained period of 2 years, improved many cardiometabolic risk factors, namely:

• Blood pressure
• Plasma lipids
• C-reactive protein
• Glucose homoeostasis

Because studies of CR on lifespan in animal models start early in the lifespan, to understand similar effects in humans, the investigators conducted the experiment in similarly young, healthy individuals (aged 21-50 and did not have obesity). This study was the first well-powered intervention (intention-to-treat, n=218), of relatively long-term duration. Whilst the intervention procedure required 25% reduction in daily calorie intake, a modest reduction of 11.9% was observed but more importantly demonstrated beneficial adaptations, even when controlling for relative weight loss changes. Furthermore, the improvements in cardiovascular health factors typically became evident within a 2–4-week period and then dissipated over a period of several weeks after resumption of a normal diet. [Note: if you want to hear more about the CALERIE trial, you can listen to a discussion of it with one of the authors Dr. Eric Ravussin in episode 92 of the podcast.]

Another RCT, the FEELGOOD trial, followed a crossover design to evaluate one 24-h period of fasting and 1 day of ad libitum feeding. In FEELGOOD, fasting resulted in a marked but short-term increase in human growth hormone, red blood cell count, and total cholesterol (resulting from increases in both LDL cholesterol and HDL cholesterol, despite substantially decreased triglycerides). The findings of human trials may be useful in developing longer-term trials.

Fasting Interventions in Cancer Patients

The DIRECT trial was a multi-centre, randomised trial which aimed to evaluate the impact of the FMD on tolerance to, and efficacy of, neoadjuvant chemotherapy (i.e. chemotherapy given as a first step to shrink a tumor before the main treatment) in women with stage II or III breast cancer. DIRECT showed that a FMD exerts protective effects, not only to toxicity to chemotherapy but also on radiology and pathology responses.

All fasting and cancer trials to date have focused on assessing the safety and tolerability of fasting regimens or drug therapies that induce a metabolic response that mimics fasting. Ongoing trials, aimed at assessing efficacy of FMD in cancer treatment (for various tumour types) and prevention or re-occurrence of tumours as well as identification of biomarkers, are ongoing and offer an exciting opportunity. To our knowledge, no studies have yet determined if fasting affects cancer recurrence in humans.

Clinical investigations of the effectiveness of fasting in cancer patients to date have focused predominantly on safety assessment. For the most part, it has been demonstrated that such interventions don’t negatively impact patients nutritional status, in those who are not at nutritional risk. In one clinical trial, Valdemarin et al., 2021 reported only a few mild side effects when a 5-day FMD intervention was administered in cancer patients (solid or hematologic malignancy) actively receiving treatment. Patients who received a 5-day FMD adjunct therapy on average 6.3 times over the duration of study (once per month, at 3 week cycles), experienced reduced fat mass, insulin production and a reduction in inflammatory markers. Some potential negative side effects of modified fasting regimens and changes in body composition have been observed. It may be potentially overcome with multimodal intervention, combining fasting regimens with resistance training.

Conclusions

1) Unfortunately, various fasting “protocols” or diets have appeared in the popular press with headlines or claims that are largely inaccurate. Often this leads to the lines between popular diet books or blogs and actual valid research becoming blurred in many peoples mind.

2) Most of the fasting and longevity research has been in animals, and evidence in humans that is suggestive of increased healthspan is exciting, but very preliminary.

3) Of the human evidence that does exist, much of that supports a role for increasing healthspan via improving cardiometabolic health, of which age is a risk factor. However more evidence is required for its direct effects on the incidence or severity of other age-related illnesses, such as dementia.

4) The considerable heterogeneity in the types of fasting strategies employed in human and animals’ studies, and in reporting of health outcomes brings challenges. Well-designed RCTs using valid comprehensive, standardised assessments, are required to determine if fasting improves healthspan and contributes a viable component of lifestyle approaches to maintain life beyond a typical lifespan of 75-85 years.

5) Evidence in other disease states, such as adjunct cancer therapy is promising and may offer new opportunities for improved survival rates in some certain types of cancer and/or tumour. The types and individuals it may likely give rise to benefits, is still under investigation. That said, safety evidence of FMD regimens have delivered good evidence for it’s low risk potential, under clinical guidance.

About this Statement

• Lead on Research & Writing: Niamh Aspell, PhD
• Reviewing & Additional Commentary: Alan Flanagan
• Editing: Danny Lennon

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Podcast episodes related to this topic

• Episode #92: Eric Ravussin, PhD – Calorie Restriction, Longevity & Hormesis
• Episode #175: Prof. Klaas Westerterp – Metabolism, Energy Expenditure & Weight Regulation
• Episode #399: Prof. James Betts – Does Fasting Have Benefits Beyond Those Caused By Calorie Restriction?
• Episode #302: Leonie Heilbronn, PhD – Alternate-Day Fasting, Early Time-Restricted Feeding & Caloric Restriction