The effect of diet on aging and longevity - should nutritionists advise intermittent fasting?

Highlights:

• It is proven that restriction of calories without malnutrition prolongs the mean and maximal lifespan
• There is a variety of Intermittent fasting diet types such as complete alternate day fasting, modified alternate-day fasting, and  time-restricted feeding (TRF)
• Intermittent fasting is beneficial due to weight loss, blood sugar, and insulin levels regulation and sirtuins expression

Introduction

Modern society now lives the longest and the healthiest in the history of humanity. Our longevity is of course strongly affected by access to medicine and pharmaceuticals, food and clean water source, increased hygiene, and overall understanding of what is good and bad for our organisms thanks to science. It seems that we already cracked the code for disease prevention. But science has only scratched the surface of knowledge about aging and longevity. We want to focus here on the dietary impact on longevity and aging and provide guidance for nutritionists.

The lifestyle has an impact on aging

Aging, defined by WHO, is the impact of the accumulation of a variety of cellular and molecular damage over time that reduces well-being due to causing disease. Aging patterns are believed to be partly encoded in our genes but also influenced by environmental factors. Cellular and genetic damage leads to a decrease in the mental and physical capacity of the body and increases the risk of disease and death. Aging relates to so-called geriatric syndromes such as hearing and vision loss, osteoarthritis, diabetes, or dementia. Scientists nowadays are intensively researching not only how to treat those diseases but also how to prevent them. And how to slow down aging, both through medicine and lifestyle as well.

You are what you eat

First scientific articles speculating the connection between diet and longevity appeared more than 80 years ago. Research done on rats by McCay, Crowell, and Maynard in 1935 states that the restriction of calories without malnutrition prolongs mean and maximal lifespan compared with ad libitum (unrestricted) feeding (1). Since then, the dieting trends and recommendations have been changing countless times but with one rule always staying the same. Do not overeat. There is no one miracle diet to slow down aging but it is proven that calorie restriction leads to a prolonged lifespan in a variety of organisms. Mice that have been on a calorie-restricted diet all their life had different gene expression patterns than the standard mice. Especially genes correlated with life extension, such as those related to DNA repair and stress and immune responses were impacted by calorie restriction. This suggests that restricted calorie intake can trigger a genetic response that postpones aging (2). Strongly suggested are the Mediterranean, Okinawan, or DASH (Dietary Approaches to Stop Hypertension) diet. All of the above share a few features: a big intake of unrefined carbohydrates, moderate protein consumption from sources such as vegetables/legumes, fish, and lean meats, and a healthy fat combination, rich in omega-3, with a higher intake of mono and polyunsaturated fats than saturated fat. Such a fat combination in a diet is beneficial for reducing inflammation and optimizing cholesterol levels. Moreover, plant-rich diets have lower caloric density but are rich in phytonutrients and antioxidants. Changing eating habits for one of these diets result in a low glycemic load, less inflammation, and oxidative stress. It can help the prevention of age-associated diseases and support healthy aging and longevity (3).

It is important when you eat

Humans evolved in environments where food was not as easily available as now. Our bodies through years of evolution developed adaptations enabling us to function well in a food-deprived state. Keeping this in mind, fasting and calorie intake reduction have been researched to observe its potential on human longevity. The goal was to understand if the time we eat and not what we eat can improve our lifespan. Intermittent fasting (IF) can be described as an eating pattern with extended periods (e.g., 16 – 48h) with little or no energy intake alternating with periods of normal calorie intake. Intermittent fasting can be categorized into 3 main types:

• Complete alternate day fasting - alternating fasting days with only no-energy foods/beverages consumption with eating days with unlimited food and drink consumption.
• Modified alternate day fasting - allows consumption from 20 to 25 % of energy demand on fasting days. It is the basis of the 5:2 diet, composed of 2 uninterrupted days a week with severe energy restriction and the remaining 5 days of unrestricted feeding. Alternate day fasting regimes are also called periodic fasting (PF).
• Time-restricted feeding (TRF) - is the restriction of the eating period to 8 or fewer hours per day, continuously (4, 5).

Outside of these 3 main types, there are also prolonged fasts such as 3-5 day fasts with no calorie intake a few times a year and others. All the fasting-connected eating patterns have been proven to have a beneficial impact on health in both animal and human studies. Mice and rats introduced to IF in the early life stage have been living longer than the ones that had unlimited access to food. All described fasting patterns according to research can counteract disease processes of age-related disorders (6).
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Intermittent fasting’s impact on health and longevity

Intermittent fasting generally supports weight loss and leads to many metabolic changes. Obesity is one of the biggest risk factors for the development of health problems such as insulin resistance which can lead to life-shortening (7). Therefore, intermittent fasting was tested in overweight and obese subjects. IF leads the organism to use fat as the major energy source instead of using glucose. This metabolic state in which the body uses fat and ketones rather than glucose as the main fuel source is called ketosis. Studies highlighted that those overweight subjects exhibit weight loss, lowering of serum cholesterol and triglycerides levels, better glucose homeostasis, and higher ketone levels. All these metabolic changes lead to the prevention of metabolic syndrome and improve longevity (6, 8). Fasting supports lower blood glucose levels in the low normal range and lower insulin levels. Insulin sensitizing effect that leads to reduction of insulin resistance was detected as well. Together with the elevation of adiponectin and reduction of circulating leptin all the above changes can help type 2 diabetes prevention, and in return lower the risk of cardiovascular diseases. It was observed that intermittent fasting subjects have lower resting heart rate and blood pressure. Reduction in levels of inflammation markers such as CRP, TNF-α, and IL-6 and cancer risk biomarkers have been observed which may play a beneficial role in cardiovascular diseases and cancer prevention (6, 9, 10).

An interesting study was done to research the influence of IF on oxidative stress and the regulation of genes related to aging. Patients that were consuming in consecutive days 25 % and 175 % of normal calorie intake for 3 weeks period exhibited higher levels of reactive oxygen species (ROS) meaning that the patients were experiencing oxidative stress. This increase of ROS leads to a clever mechanism in mitochondria. ROS enhance the expression of proteins called sirtuins that are involved in many processes lying behind extended lifespan. Sirtuins prompt protective adaptive response to oxidation stress by activating expression of ROS scavengers, which leads to blocking of ROS negative impact (11). But this is not the only impressive feature of sirtuins. They are also involved in DNA damage repair promotion and DNA conservation, suppression of chronic inflammation, neuroprotection, and prevention of most of the above-described age-related diseases. In conclusion, sirtuins are acting as an anti-aging and life-expanding agent (12). In conclusion, intermittent fasting can improve our longevity by increasing the expression of sirtuins.

The impact of IF and calorie restriction on cognition has been studied in mice. 3 months of IF increased long-term memory retention, adult hippocampal neurogenesis, and expression of longevity genes. Both calorie restriction and IF improved the mice's ability of learning (13). Also, some sirtuins, particularly sirtuin 1, and 3 have been related to neuroprotection. Sirtuin 2 is involved in myelin production in Schwann cells (12). These findings suggest that intermittent fasting can be beneficial for the health of our brains and help to counteract neurodegenerative disorders such as Alzheimer’s disease (AD) (6). There is a close correlation between Alzheimer’s disease and insulin signaling abnormalities connected with diabetes, so much that AD started to be called “diabetes type 3” or “brain diabetes”. IF in this case by having a positive influence on insulin and blood glucose levels protects our brains (14).
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Is intermittent fasting safe? 

There is still not enough research done to understand the long-lasting results of intermittent fasting. Many tests are yet to be performed to distinguish IF’s safety because the mechanisms behind the fasting benefits are still poorly understood. Most of the clinical tests have been done only once, and never repeated to confirm the results. Therefore, intermittent fasting as well as dieting in general should always be introduced with caution and after proper preparation to improve our longevity instead of getting the opposite effects.

Intermittent fasting is safe for most people but not for everyone. It was distinguished that time-restricted eating can decrease lymphocytes and natural killer cell counts which can negatively impact immunity and protection against infections. Daily fasting periods lasting 14 h or more can also be associated with gallstone formation (9). Fasting would be extremely difficult and risky for patients dealing with obesity as well as diabetes and is not recommended to pregnant women, people struggling with eating disorders, ones that have recently undergone a surgical procedure, and people in poor overall health. Peptic ulcers, liver, and kidney diseases are contradictions too. This means that diet change and calorie intake regime should always be consulted with a physician and nutritionist and be introduced slowly.

Overall, a healthy diet and intermittent fasting are considered safe approaches to a healthier and longer life (5).  We all must eat to live and the way we eat and what we eat has an incredible influence on the lengths and quality of our life. And to sum up, being moderate with food and investing in smaller plates will make life healthier and longer.

1.           McCay CM, Crowell MF, Maynard LA. The Effect of Retarded Growth Upon the Length of Life Span and Upon the Ultimate Body Size: One Figure. The Journal of Nutrition. 1935;10(1):63-79.

2.           Passarino G, De Rango F, Montesanto A. Human longevity: Genetics or Lifestyle? It takes two to tango. Immun Ageing. 2016;13:12.

3.           Willcox DC, Scapagnini G, Willcox BJ. Healthy aging diets other than the Mediterranean: a focus on the Okinawan diet. Mech Ageing Dev. 2014;136-137:148-62.

4.           Patterson RE, Laughlin GA, LaCroix AZ, Hartman SJ, Natarajan L, Senger CM, et al. Intermittent Fasting and Human Metabolic Health. J Acad Nutr Diet. 2015;115(8):1203-12.

5.           Nowosad K, Sujka M. Effect of Various Types of Intermittent Fasting (IF) on Weight Loss and Improvement of Diabetic Parameters in Human. Curr Nutr Rep. 2021;10(2):146-54.

6.           Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.

7.           Printz C. Extreme obesity may shorten life expectancy up to 14 years. Cancer. 2014;120(23):3591.

8.           Kane AE, Gregson E, Theou O, Rockwood K, Howlett SE. The association between frailty, the metabolic syndrome, and mortality over the lifespan. Geroscience. 2017;39(2):221-9.

9.           Crupi AN, Haase J, Brandhorst S, Longo VD. Periodic and Intermittent Fasting in Diabetes and Cardiovascular Disease. Curr Diab Rep. 2020;20(12):83.

10.        Liu B, Page AJ, Hatzinikolas G, Chen M, Wittert GA, Heilbronn LK. Intermittent Fasting Improves Glucose Tolerance and Promotes Adipose Tissue Remodeling in Male Mice Fed a High-Fat Diet. Endocrinology. 2019;160(1):169-80.

11.        Wegman MP, Guo MH, Bennion DM, Shankar MN, Chrzanowski SM, Goldberg LA, et al. Practicality of intermittent fasting in humans and its effect on oxidative stress and genes related to aging and metabolism. Rejuvenation Res. 2015;18(2):162-72.

12.        Watroba M, Szukiewicz D. The role of sirtuins in aging and age-related diseases. Adv Med Sci. 2016;61(1):52-62.

13.        Dias GP, Murphy T, Stangl D, Ahmet S, Morisse B, Nix A, et al. Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho. Mol Psychiatry. 2021.

14. Stanciu GD, Bild V, Ababei DC, Rusu RN, Cobzaru A, Paduraru L, et al. Link Between Diabetes and Alzheimer's Disease due to the Shared Amyloid Aggregation