#435: Fasting & Longevity – Does the Evidence Match the Hype?

1. Detailed Study Notes
2. Transcript

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The key idea for this episode relates to reductionist thinking that comes from hyper-focusing on mechanisms and looking at them over-simplistically.

One of the best examples of this comes in discussions of fasting and “anti-ageing” where the process of autophagy is brought up.

Autophagy is a process within cells that removes damaged cell organelles and proteins, as well as eliminating pathogens in the cell. And so this adapative process does indeed play an important role in human health and biological function.

It has unfortunately become a buzzword used by those advocating for fasting protocols as a means to enhance longevity, decrease biological age or to “rejuvinate” the body in some manner.

The reductionist thinking goes along the lines of:

• Fasting = more autophagy
• Autophagy = good
• More fasting = more beneficial health

Clearly this over-simplfying a complex biological process.

This thinking emerges from looking at the impact on certain nutrient sensing pathways in the body during fasting. So during a fast, with the lower levels of amino acids and glucose, there is a reduction in mTOR pathway activity, and an increase in AMPK activity. This can lead on to an upregulation of authophagy.

However, there are number of issues to consider:

1. Autophagy is a process that occurs without fasting too. For example, exercise enhances autophagy much more so than fasting (as well as actually having evidence for a whole host of potent health-promoting effects).
2. Measurement of autophagy is practically impossible.
3. Autophagy is tissue-specific. And so thinking of “autophagy = good” just lacks context.
4. Speaking to this context, some disease states show increases autophagic activity in affected tissues.

Most importantly, we should ask: does fasting lead to actual enhanced longevity in humans, with increased autophagy playing a causal role?

We could also see mechanisms being over-simplified when cellular senescence is discussed. In a similar fashion, this is indeed a real process. However, the question remains the same; does fasting enhance longevity in humans, via an ability to clear out senescent cells to a greater degree than if not fasting?

For more on cellular senescence, see the detailed study notes.

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What is Longevity? What is Ageing?

Longevity:
The capability of an individual to survive past the (median) average age of death. If talking at a species level, it would relate to the period of time a member of that species would be expected to live under typical or ideal conditions.

You may see the term “exceptional longevity” used to describe people that live well beyond normal life expectancies. Specifically, this term is defined as surviving and living independently at age 95 and older. However, it’s important to note that this is largely a result of genetics. And in lieu of genetic manipulation, then dietary changes are not going to be what causes one to achieve exceptional longevity.

“Ageing” (usually written as “aging” in North America) has no singular definition of ageing as it can be considered in multiple ways (i.e., behavioural, physiological, cellular etc.). Usually in conversations of longevity or “anti-ageing” what is being discussed is biological ageing.

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”

So we can think of biological ageing as a progressive decline in the ability to maintain biochemical/physiological function. Importantly therefore, this is distinct from “lifespan”, which simple describes the period of time which the person is alive, irrespective of function.

So in order to account for morbidity (having a disease or significant loss of function), one may wish to consider “healthspan”, which is the period of life spent in good health, free from the chronic diseases and disabilities related to ageing (Kaeberlein, 2018).

Even in the absence of disease, all physiological systems decline in both capacity and function as we age. Of course, the rate of decline will vary and is dependent on many factors, such as genetics, lifestyle, and the environment.

Cellular Senescence

• Certain stressors (e.g. radiation exposure, chemotherapy and metabolic stress, including high-fat diet) drive formation of senescent cells
• Senescent cells cease to divide and they excrete inflammatory cytokines
• Inflammation created by senescent cells can lead to tissue dysfunction and turn healthy cells senescent
• So… it can be hypothesised that removing senescent cells may enhance health span
• How can senscent cells be cleared?
  • Some evidence for both senolytic drugs and exercise
  • Fasting has been hypothesised as another potential method, but strong evidence is lacking

Why Has Fasting Been Suggested?

Fasting has also been explored as a potential approach that could promote longevity and/or extend healthspan. This is based on a number of mechanisms by which fasting could repair cells, remove damaged cells, renew stem cells and upregulate/downregulate pathways associated with biological ageing.

Some of the most commonly discussed mecahnisms relate to the reduced levels of glucose and amino acids during fasting, which result in:

1. Reduced activity of the mTOR pathway (and increased AMPK activity)
2. Up-regulation of autophagy

Autophagic activity seems to decline with ageing.

Autophagy: A process within cells that removes damaged cell organelles and proteins, as well as eliminating pathogens in the cell.

While autophagy does indeed occur and is an important process, it has unfortunately become a buzzword in pseudoscientific nutrition circles. The reductionist thinking of “more autophagy = better” and “fasting = autophagy” is divorced from what is actually known, for example:

• While it’s generally a good thing, in some conditions increased autophagy is a problem
• It’s tissue-specific
• Measurement is difficult (virutally impossible in most settings)
• Autophagy is a process that occurs even without fasting (for example, exercise is a much more potent stimulator)

More importantly we need to ask: “does targeting autophagy via fasting lead to meaningful health outcomes?”

Other mechanisms that get discussed are those associated with nutrient sensing pathways such as insulin and IGF-1. In addition to pathways like mTOR and AMPK, other factors include FOXOs and sirtuins.

Dietary Restriction

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.

Looking at dietary restriction for longevity has its origins in work on caloric restriction, which has shown an ability to increase lifespan in a number of organisms including yeast, fruit flies and rodents.

Other work focused on restricting certain nutrients, with protein or certain amino acids often being the target based on the impact on some of the pathways mentioned earlier.

Fasting is an intervention that has garnered much recent interest.

Fasting

On a practical level, fasting can be simply thought of as not consuming energy/nutrients for an extended period of time.

Technically, from a metabolic point of view, the fasting state is called the postabsorpative state. This occurs when the food has been completely digested, absorbed, and stored.

There are many different types of fasting interventions, and depending on the specific protocol fasting may or may not include caloric restriction.

Examples of different fasting interventions:

• 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.
• Alternate day fasting (ADF): Alternating between fasting days (typically 500 kcal or less) and ‘feeding’ days (eating ad libitum).
• “5:2 Diet”: Commonly in studies IF 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. This was popularized to the mainstream in 2012 by a BBC documentary from Dr. Michael Mosley, and subsequent books that followed based on the “5:2 diet”.
• Fasting mimicking diet (FMD): Developed and investigated primarily by Professor Valter Longo and his group at the University of Southern California. 30–50% of normal caloric intake for 4–7 consecutive days, followed by a refeeding ad libitum period (typically repeated monthly).
• Prolonged fasting: This usually refers to fasting periods of 48 – 120 hours.

So can fasting increase lifespan and maintain (or increase) healthspan while doing so?

Animal Studies

Extension of lifespan and healthspan via CR have been demonstrated in many non-human models, including yeast, mice, and monkeys.

Fontana et al., 2010 describe how a healthy lifespan is under the influence of multiple nutrient pathways, rather than a single pathway.

CR & Rhesus Monkey Studies

• Two studies (> 20 years) run almost in parallel, starting in 1987, examined the impact of CR on rhesus monkeys:
  1. Coleman et al., University of Wisconsin:
     • Demonstrated delayed disease onset and mortality.
     • 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.
  2. Mattison et al., 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
  • Environmental factors

Fasting Mimicking Diet in Animal Models

• Much evidence in mice, with a lot of the work done on cancer.
• Suggests the FMD may help healthy cells (but not cancer cells) be more resistant to the effects of chemotherapy.

Human Studies

Two observational studies by Horne et al. may give some clues as to how fasting could impact major adverse clinical outcomes in humans:

1. A 2008 study on Mormons
2. A 2012 study by the Intermountain Heart Collaborative Study Group

These studies were not based on CR but on reduced tobacco use…

The first study wanted to asses whether the low coronary artery disease (CAD) risk observed in members of the Mormon church was attibutable to the fact they do not smoke.

• They had a lower risk of CAD, despite adjustment for smoking.
• Patients who reported routine fasting had lower odds of CAD than did those who did not fast.
• Those of religious preferences other than LDSs who reported routine fasting also benefited.

The second study found that patients who fasted routinely had lower diabetes risk and confirmed the first study’s findings for lower CAD risk.

CALERIE Study

Kraus et al., Lancet Diabetes Endocrinol. 2019 Sep;7(9):673-683

• Multi-centre RCT
• The investigators conducted the experiment in similarly young, healthy individuals (aged 21-50 and did not have obesity).
  • This is an important point, as studies showing benefit of CR on lifespan in animal models typically start early in the lifespan. So intervening with such an intervention too late in the lifespan may not be able to impart those benefits.
• 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
• The beneficial adaptations were evident even when controlling for relative weight loss changes.
• However, the improvements in cardiovascular health factors (which typically became evident within a 2–4-week period) dissipated within a number of weeks of the participants resuming their normal diet.

Hear more: One of the authors of the trial, Dr. Eric Ravussin, discussed it in episode 92 of the podcast.

FEELGOOD Trial

Horne et al., Nutr Metab Cardiovasc Dis. 2013 Nov;23(11):1050-7

• Followed a crossover design to evaluate one 24-h period of fasting and 1 day of ad libitum feeding.
• 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].

InterFAST Study

Stekovic et al., Cell Metab. 2019 Sep 3;30(3):462-476.e6

• Two parts (see diagram below)
• First a cross-sectional study (A) looking at people who had already been doing Alternate Day Fasting for more than 6 months.
• Followed by the control group in the cross-sectional study being transferred to a RCT of ADF vs. control.
• ADF:
  • Fasting days = water only
  • Feeding days = typical habitual diet
• Unsurpisingly there was significant weight loss in the RCT (via an average decrease of 34% weekly kcal intake compared to baseline).
• In relation to speculative mechanisms related to ageing, the authors noted that with each fasting window (36 hours) there was an average 20% decrease in many amino acids or related metabolites (e.g., ornithine, citrulline, and taurine). This has some parallel to the observation in experimental animal models that a low systemic concentrations of amino acids (especially methionine) have been shown to be sufficient for lifespan extension.

FMD & Cancer

To date, all fasting and cancer trials have focused on assessing the safety and tolerability of fasting regimens or drug therapies that induce a metabolic response that mimics fasting.

Currently, there are a number of ongoing trials, aimed at assessing efficacy of FMD in cancer treatment (for various tumour types) and prevention or re-occurrence of tumours.

While there is much hope and excitement in this emerging area, to our knowledge, there are currently no studies that have determined if fasting affects cancer recurrence in humans.

The types and individuals it may likely give rise to benefits, is still under investigation.

DIRECT Trial

• Examined impact of the fasting-mimicking diet on tolerance to, and efficacy of, neoadjuvant chemotherapy in women with stage II or III breast cancer.
  • [neoadjuvant chemotherapy = chemotherapy given as a first step to shrink a tumor before the main treatment]
• Showed that a FMD exerts protective effects, not only to toxicity to chemotherapy but also on radiology and pathology responses.

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.

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