The benefits of a calorie restriction diet are profound when it comes to improving health and longevity. It’s currently one of the most effective methods to not only prevent the diseases of aging but also treat and reverse some diseases like diabetes. The beneficial effects of CR are also backed up by decades of research in lab animals, and more recently in humans.

What is Calorie Restriction?

Calorie restriction is a diet whereby you reduce calorie intake without becoming deficient in essential vitamins, minerals, fats, and protein. A reduction in calorie intake could be as little as 10% from your baseline intake or as much as a 50% reduction in calories.

In many animals, there is a correlation between the degree of restriction and the extension of mean and maximum lifespan. Meaning, if you restrict an animal by 30% it will on average life 30% longer.

Calorie restriction is the ‘gold standard’ of life-extending interventions that do not involve drugs or genetic manipulations.

The diet has been shown to extend the lifespan of various organisms like yeast and worms, spiders, and flies. It is also effective in mammals, with CR showing life-extending effects in mice, rats, dogs, cows, and rhesus monkeys.

The evidence in various insects and animals is overwhelming, and the evidence in humans also looks very promising.

Dr. Luigi Fontana goes into the effects of calorie restriction on health and longevity in this 1-hour video.





Benefits of calorie restriction in humans

Calorie restriction has been practiced by thousands of people all around the world for many decades. It was first popularized by Dr. Roy Walford. He himself underwent calorie restriction when he entered Biosphere 2.

It was the data from this experiment which aimed to look at the sustainability of a colony on another plant that we saw the first solid evidence in humans that CR improves health as it does in rodents.

Roy Walford went onto publish books about calorie restriction and then a movement was born. The CR Society, which is a non-profit organization, helped people who were interested in CR keep in touch with each other on an email list and forum.

In the early 2000s, several people from the CR Society were followed by Dr. Luigi Fontana at Washington University in St Louis. The results obtained from people on CR were incredible. CR appeared to dramatically lower the risk of disease in humans.

Calorie restriction prevents heart disease, diabetes, and stroke – WUSTL Studies

Cardiovascular disease is one of the biggest killers in the world. Although we have made great progress in lowering the number of people dying from heart attacks, the number of people developing the disease continues to rise. A CR diet may be one of the most powerful ways to prevent this disease according to research conducted in humans.

In a study published in 2004, 18 individuals who had been on a calorie restriction diet for an average of 6 years were studied and compared to a control group who were on a standard western diet. Those in the CR group also had data from previous medical records to show what their numbers looked like before they went on the diet.

As expected, the calorie restriction group were significantly lighter than the control group. The CR group had a BMI of 19.6 vs 25.9 for the WD group.

Health Parameter Calorie Restriction Group (n=18) Control Group (n=18) Total Cholesterol 158 +/- 39 205 +/- 40 LDL Cholesterol 86 +/- 28 127 +/- 35 HDL Cholesterol 63 +/- 19 48 +/- 11 Triglycerides 48 +/- 15 147 +/- 89 Systolic Blood Pressure 99 +/- 10 129 +/- 13 Diastolic Blood Pressure 61 +/- 6 79 +/- 7

The data in this table is from 2014 published study: long-term calorie restriction is highly effective in reducing the risk of atherosclerosis in humans (source).

Cholesterol and blood pressure in people on CR

In the paper, it is mentioned that those on a CR diet had total cholesterol and an LDL cholesterol level that fell into the lowest 10% for their respective age group.

Their triglyceride levels were also remarkably low, falling into the lowest 5% of 20-year-olds, despite their average age being 50 years old. The CR group also had very high good cholesterol (HDL) for their age group, being 85-90 percentile range US men.

Blood pressure readings for the CR group was also very low and equivalent to that of someone who is 10 years old, but none of them had any symptoms of orthostatic hypotension.

As impressive as those findings were, the CR group also had remarkably low levels of inflammation, measured by looking at C-Reactive Protein, and also lower fasting and insulin levels compared to the control group.

People on CR were able to obtain their previous medical records and these clearly show that CR was responsible for these effects. Prior to calorie restriction, many of the individuals displayed similar profiles to that over the control group in the WUSTL study [1].

Calorie restriction keeps the heart and arteries young

And if those results weren’t impressive enough, the study found that none of the individuals on calorie restriction any evidence of plaque formation in the carotid artery. It was 40% less thick than the arteries from the control group, meaning that the people on CR had almost no risk of having a heart attack or stroke [1].

In a later study at WUSTL, 22 people on a CR diet were monitored to look at the effect of the diet on their heart function.

The study found that people on CR (ages 35-85) had a heart rate variability score that was 20 years younger than their age. And given the fact that those in the study were on CR for an average of 7 years, it showed that calorie restriction was able to effectively prevent and reverse the deterioration of heart rate variability in humans [2].

In a separate paper, it’s reported that diastolic function of people on calorie restriction was 15 years younger than their age! [3].

Calorie restriction induces a younger gene expression profile in humans

Although calorie restriction can result in reduced muscle mass, the diet is able to preserve the quality and function of muscle with age. In rhesus monkeys, calorie restriction appeared to delay the onset of sarcopenia with age, and this is similar to what is seen in mice that are subjected to CR [4]. If these results were to translate into humans, calorie restriction could significantly enhance the mobility and quality of life in old age.

In 2013, a study was published where researchers looked at the effects of long-term CR (9.6 years on average) on muscle transcriptional profile. They found that many of the genes associated with health and improved longevity were up-regulated by 30% calorie restriction. Two of the genes which were up-regulated by CR were FOXO-3A and FOXO-4.

These genes appear to be important for longevity in animals and also have been implicated in extreme human longevity.

In summary, the researchers saw that several longevity pathways/genes were up-regulated by CR

Increased expression of SOD2 – Antioxidant enzyme (2.2 fold increase).

– Antioxidant enzyme (2.2 fold increase). Increased expression of DDB1 – Repairs DNA (1.7 fold increase).

– Repairs DNA (1.7 fold increase). Decreased expression of cyclin D2 – Important for cell cycle progression (13 fold decrease!).

– Important for cell cycle progression (13 fold decrease!). Increased expression of genes involved in autophagy – Recycles damaged cells and organelles: beclin -1 (1.5 x). LC3 (1.7x), autophagin-1 (1.5x).

Recycles damaged cells and organelles: beclin -1 (1.5 x). LC3 (1.7x), autophagin-1 (1.5x). Increased SIRT2, SIRT4, SIRT5 (3.4, 3.0, 2.2 fold increase).

(3.4, 3.0, 2.2 fold increase). Decreased expression of inflammatory genes (1.5 fold decrease in Nf-kappaB).

(1.5 fold decrease in Nf-kappaB). Decreased insulin/IGF-1 pathway (causes a decrease in mTOR and increased expression of FOXO3A protein).

source of data: “calorie restriction induces a younger transcriptional profile in skeletal muscle.”

One of the amazing findings from the study was that the calorie restriction group had a similar transcriptional profile as the younger control group. The researchers recruited two controls for the study: one control group who were age-matched with the CR group and a young western diet group aged 31 years.

The muscles from CR subjects looked much more similar to muscles of young adults than the age-matched (58 years) control group [5, Figure 5a].

These results suggest that humans on CR have a similar response to the diet as mice and rats on the diet who go on to have better health and longer life.

Longevity is in the “gene expression”

The extension of lifespan from calorie restriction is thought to be down to a well-orchestrated response by the body to beef up repair and maintenance. There are several genes that have been identified in humans that appear to significantly protect them against diseases of aging.

For example, several studies now have confirmed the link between FOXO-3A and longevity. Many variants of this ‘longevity gene’ have been studied and certain types appear to be more frequent in increasingly older individuals.

The effects of this gene are numerous: it activates protective mechanisms increasing autophagy, increasing DNA repair, increasing antioxidant response (SOD2) and reducing cell cycle progression.

Autophagy genes and longevity – Damaged and senescent cells can be cleared and recycled by a process known as autophagy. In recent years, it’s become clear that senescent cells play an important role in age-related disease and therefore finding ways to increase autophagy could be important for longevity.

In 2014 a study was published looking at beclin-1 (a gene up-regulated in humans on CR) on human longevity. One of the reasons the researchers looked at this gene is because dysregulation of beclin-1 has been associated with disorders such as cancer, neurodegeneration and increased invasion of pathogens.

They looked at three groups, the centenarians (aged 100-104) and two control groups: one healthy group (27-39 years) and another group who had a myocardial infarction at a young age. Centenarians in the study were found to have significantly higher levels of beclin-1 (2.2 ng/ml) compared with young healthy controls 1.4 ng/ml).

The researches concluded that increased autophagy might be associated with extreme longevity potential [14].

Adding to these findings, a more recent study published in 2018 showed that several genes involved in autophagy were up-regulated in the group of 76 centenarians [15].

Calorie restriction induces a health phenotype that is similar to or better than the phenotype induced by nonagenarians/centenarians and their offspring’s genotype

It’s common knowledge that the offspring of centenarians display more favorable health biomarker profile that appears to protect them from common age-related diseases such as Heart disease, Stroke, Diabetes, Cancer, Alzheimer’s, and Immunological aging.

There is not just one gene involved in increasing the chances of becoming a centenarian or supercentenarian in these people, but many favorable gene variants which are protective against aging.

It’s predicted by some that people on calorie restriction will have a significantly longer lifespan than the current average in the west of about 80 years.

In humans who are practicing 30% calorie restriction, there is very little to no risk of diabetes, stroke, or cardiovascular disease. These three alone make up a significant portion of deaths in older people and these diseases are significantly delayed, diminished in severity or completely prevented in people predisposed to longevity because of genetic factors.

What is amazing is that not only do people on calorie restriction display an extremely favorable risk profile for disease, the biomarkers that appear to be relevant for increasing health and survival go in the same direction for CRONies and offspring of nonagenarians (NA) and centenarians (CO).

Another exciting fact is when comparing the data from closely age-matched individuals of people on CR to CO, it appears that in many cases, CR has a more powerful effect on improving health biomarkers than simply being ‘genetically lucky’.

In the table below I have included data from a study on CRONies (Fontana, 2004) as well as data from the Leiden longevity study (LLS) cohort. These people have a history of familial longevity. The study also includes data (not shown) from various age groups ranging from <50 to over 90 years of age.

Health Parameter Calorie Restriction Group (WUSTL) (n=18) Offspring of Nonagenarians (LLS) (n=1602) LLS Partners (n=327) Age 50 Years 59 Years 55 (50-60) Total Cholesterol 158 +/- 39 216 +/- 43 218 +/- 41 LDL Cholesterol 86 +/- 28 128 +/- 35 130 +/- 35 HDL Cholesterol 63 +/- 19 56 +/- 17 56 +/- 18 Triglycerides 48 +/- 15 155 +/- 91 165 +/- 107 Systolic Blood Pressure 99 +/- 10 142 +/- 19 138 +/- 20 Diastolic Blood Pressure 61 +/- 6 ??? ???

Column 3 (LLS) and column 4 (LLS) is data from a 2015 paper called: “LDL cholesterol is still a problem in old age? A Mendelian randomization study” (source)

As you can see in the above table, people on CR have a much better CVD risk profile than the general population and even offspring of nonagenarians or families that have a history of familial longevity.

In the paper that this data was obtained from the researchers were looking at the relationship between genetic LDL risk score and mortality.

A higher number of LDL increasing alleles was associated with a higher mortality rate. They found that those who lived up to age 90 tended to have a lower frequency of LDL increasing alleles.

Over the last few years, data has come out showing that low LDL might be a risk factor for death in old age. However, the data from this study shows that a lifetime of lower LDL cholesterol leads to a longer life.

Simply put: life-long low LDL cholesterol is not a risk factor for mortality and is associated with increased survival at all ages, even in the old [7].

Low thyroid function and body temperature for extreme longevity

Low thyroid function has been linked with longevity in both animals and humans. A study published in 1986 showed that by inducing hypothyroidism in rats (T4 level 2/3 of normal), you could extend their lifespan by four months [8].

Compared to Growth hormone-deficient Ames and Snell dwarf mice, the reduction in thyroid hormone and lifespan extension is quite small, but it does show that thyroid levels could be an important signature of potential extreme longevity in humans.

Low thyroid function is characterized by having a low body temperature and low metabolic rate. This phenotype is typically displayed in animals subject to CR or genetic modification which leads to lifespan extension.

People on a long-term calorie restriction diet also have been found to have reduced free T3 levels compared with age-matched exercisers and western diet controls [9].

Serum T(3) concentration was lower in the CR group than the WD and EX groups (73.6 +/- 22 vs. 91.0 +/- 13 vs. 94.3 +/- 17 ng/dl, respectively) (P < or = 0.001), whereas serum total and free T(4), reverse T(3), and TSH concentrations were similar among groups.

In a separate paper, it was reported that calorie restriction also reduced core body temperature. People on CR had a ~0.2 Degrees Celcius lower mean 24-hour core body temperature compared to EX groups, and WD groups [10].

Both of these biomarkers have been independently shown to be associated with a longer lifespan in animals in humans. For example, in the Baltimore Longitudinal Study on Aging, they showed that lower core body temperature was one of three markers of longevity in men [11].

Multiple studies in humans have now clearly shown a relationship between predisposition to longevity and lower levels of FT3, FT4, and TSH. Lower levels of these hormones have been found in centenarians’ children, nieces, and nephews [12].

According to another paper looking at familial longevity in the Leiden Longevity Study, this ‘heritable phenotype’ with regards to lower thyroid function confers a survival advantage in old age [13].

Bottom line: Once again, calorie restriction is shown to initiate a protective phenotype in humans that mimic the phenotype or even has a stronger impact on modulating hormones related to slowing biological aging in mammals.

In my own case, my core body temperature has remained very low at 35.5 degrees C (average from several readings throughout the day) since starting CR. I’ve also had a significant decrease in free T3 and free T4, with a normal TSH. Of course, genetic factors and the severity of restriction may come into play in how some individuals respond to CR.

Is Calorie Restriction The Fountain of Youth for Humans?

Calorie restriction is clearly one of the most promising dietary interventions in humans for extending lifespan. Although there is no clear data from people on a long-term CRON diet as of yet, the data we do have suggests that CR induces a ‘longevity phenotype’ that matches closely what we see in mice and rats.

Moderate calorie restriction or a CRON diet also appears to induce a phenotype which is similar to that of centenarians or their offspring. In fact, the data appears to show that in many cases, people on calorie restriction have a much more favorable health biomarker profile than people who have a history of longevity in their family and possess ‘longevity genes’.

It’s likely that people on calorie restriction that reach 90-110 years of age will be significantly healthier than nonagenarians and centenarians who got there because they were genetically lucky.

CR seems to induce a more robust and powerful effect on health markers such as blood pressure, glucose, insulin, inflammation, reductions in thyroid hormones, body temperature, IGF-1 (with protein restriction) and other markers associated with improved health and survival.

Although centenarians may possess protective gene variants that result in a lower risk of major age-related disease, the effect on ‘health biomarkers’ (e.g cholesterol) is modest compared to the effect of calorie restriction (at least when comparing the offspring of centenarians). Since there is no 100-year-old CRON adherent currently, it’s impossible to compare directly between non-CR’d centenarians and CR centenarians.

We know that CR affects multiple pathways and genes that have been found to associated with exceptional longevity in humans. These include the Insulin/IGF-1 pathway and genes downstream from that such as the FOXO and subsequent activation of genes involved in DNA repair, autophagy, cell cycle, antioxidant defense mechanisms.

In recent years there has been a lot of exciting research looking at autophagy. And here again, centenarians (and people on CR) appear to have elevated expression of genes involved in autophagy.

It’s my belief that life-long calorie restriction (from age 20-30) is the most powerful way to reach centenarian status. The only problem we face is understanding how much CR is enough and is too much CR damaging and life-shortening.

By objectively monitoring health biomarkers as well as being mindful of subjective well-being, it might be possible to ‘adjust’ CR over time as you learn more about how you are responding to the diet (this is generally not possible in animal studies).

In the absence of future age-reversal or anti-aging therapies such as telomere gene therapy, senolytics, stem cells, NAD+ increasing agents etc, CR is likely to be the best way to break current human longevity records.

Stop monkeying around: Does Calorie Restriction work in non-human primates?

The of the longest studies on calorie restriction has been on rhesus monkeys at the NIA and Wisconsin. The results of these studies were highly anticipated but both ran into several problems early on and throughout the study. I did an analysis of both studies in 20014 that I recommend reading.

The Wisconsin study appeared to show a significant increase in healthspan and lifespan, especially when looking specifically at age-related mortality and not all-cause mortality. But there were many criticisms about the study with regards to their diet.

In the NIA group, the results were very mixed. The most recent paper showed that calorie restriction does indeed increase healthspan and lifespan when implemented in older monkeys.

The results of the study from 2017 showed that the median survival for old-onset CR was 35 years old. This is very high for rhesus monkeys when previous records show that rhesus monkeys tend to live on average 27 years.

It should also be noted that the control group in this study was restricted by 10%, and we know that in some strains of animals, 10% restriction in calories can yield a 30-40% increase in mean lifespan.

Nevertheless, 6 of the 20 calorie restriction monkeys in the old-onset group lived beyond 40 years old. And one rhesus monkey called Sherman is still alive at 43 years old!!!

To put this in perspective: It’s estimated that 1 human year = 3 for a rhesus monkey.

This means that 6 of the calorie-restricted monkeys were like Jeanne Calment’s of the monkey cohort (40 years for a monkey = approximately 120 human years).

Sherman, the rhesus monkey that is 43 years old, is equivalent to a 129-year-old human.

All that being said, the results of the study were very mixed. In many respects, the calorie restriction monkeys did not respond to CR in the way we would expect. Various biomarkers were inconsistent with what we would normally expect on CR.

It’s possible that humans respond to CR better than rhesus monkeys. Indeed, humans seem to show changes that are more consistent with what rodents show when they are put on CR than do monkeys who are put on the diet.

Finally, calorie restriction was recently shown to significantly increase the lifespan of lemur monkeys by 50%. You can read my report on that study here.

Should you try out a calorie restriction diet?

If you want to live a long and healthy life, then calorie restriction could be the best way to achieve that.

A CR diet isn’t “all or nothing”. You can try restricting just 10-15% of your calorie intake and see benefits over time.

If you have a lot of cancer, diabetes or heart disease in your family, CR will be a powerful preventative strategy. The is also very likely effective in preventing autoimmune diseases, helping with allergies, lowering the risk of dementia, osteoporosis etc.

If you’re looking at trying out a CR diet, make sure that you take things slowly. Don’t lose weight too fast, and get some baseline blood tests done so you can see and monitor improvements in health.

One of the findings from the studies done at WUSTL is that people on a CR diet also have to limit protein intake if they are to see a reduction in IGF-1 (an important marker of cancer risk and aging).

A vegan diet is thought to also help lower IGF-1 levels in humans by eliminating animal proteins that are responsible for the biggest increase in IGF-1. If you want to keep your protein to a moderate level, supplementing plant-based protein powders should have less of an effect on IGF-1 compared to whey protein.

What age should you start calorie restriction?

In animal studies, the earlier calorie restriction is started, the bigger the benefit. That being said, it’s not recommended that you start the diet before age 18-20.

Calorie restriction has been shown to work even if it’s initiated late in life. That means, if you’re around 60 years old, a CR diet can still help reduce your risk of disease (even reverse some conditions) and may add many years to your lifespan.

Longevity in Okinawa is a result of ‘mild calorie restriction’

The Island just off mainland Japan was known to be one of the few places in the world where people enjoyed much greater health and longevity. It was not uncommon to see groups of 100-year-old friends together, perhaps 4 or 5 of them living from the same village.

In 1949 Okinawan people were eating approximately 1539 Calories per day, mostly from sweet potatoes. But by 1993 that rose to around 1930 Calories per day. This makes it difficult to draw definite conclusions about the effectiveness of CR in humans since the Okinawan’s have been steadily increasing their calorie intake for decades.

Although, we can still learn some things from elderly Okinawan’s. They did display some of the typical changes that we see in humans on CR, but their diet was not perfect and studies showed that elderly Okinawan generally suffered from nutrient deficiencies.

Summary of CR benefits

This is a summary of the benefits of calorie restriction that you can expect:

Reduced risk of heart disease, stroke, and diabetes.

Reduced risk of cancer.

Reduced risk of inflammatory disorders including autoimmune diseases.

Reduction in severity or elimination of allergies like hay fever.

Reduced risk of Alzheimer’s disease.

Improved or elimination of IBD and other digestive issues.

Delayed signs of aging such as skin aging and grey hair.

Improved immune system (mostly anecdotal from reports of lower colds, flu among people on CR).

Induction of ‘longevity phenotype’ which may slow down aging.

References

1. Luigi Fontana,*† Timothy E. Meyer,* Samuel Klein,* and John O. Holloszy*

Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC404101/

2. Phyllis K. Stein Andreea Soare Timothy E. Meyer Roberto Cangemi John O. Holloszy Luigi Fontana. Caloric restriction may reverse age‐related autonomic decline in humans https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2012.00825.x

3. Meyer TE1, Kovács SJ, Ehsani AA, Klein S, Holloszy JO, Fontana L. Long-term caloric restriction ameliorates the decline in diastolic function in humans. https://www.ncbi.nlm.nih.gov/pubmed/16412867

4. Ricki J. Colman, Mark T. Beasley, David B. Allison, and Richard Weindruch

Attenuation of Sarcopenia by Dietary Restriction in Rhesus Monkeys

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812805/

5. Calorie restriction in humans inhibits the PI3K/AKT p

http://sabatinilab.wi.mit.edu/pubs/2013/Lamming2.pdf

6. J Am Geriatr Soc. 2004 Dec;52(12):2074-6.

Lower all-cause, cardiovascular, and cancer mortality in centenarians’ offspring.

https://www.ncbi.nlm.nih.gov/pubmed/15571545

7. Iris Postmus Joris Deelen Sanaz Sedaghat Stella Trompet Anton JM de Craen Bastiaan T Heijmans Oscar H Franco Albert Hofman Abbas Dehghan P Eline Slagboom Rudi GJ Westendorp

LDL cholesterol still a problem in old age? A Mendelian randomization study

https://academic.oup.com/ije/article/44/2/604/753171#91897274

8. Ooka H, Fujita S, Yoshimoto E.

Pituitary-thyroid activity and longevity in neonatally thyroxine-treated rats.

https://www.ncbi.nlm.nih.gov/pubmed/6632988/

9. Luigi Fontana Samuel Klein John O. Holloszy Bhartur N. Premachandra

Effect of Long-Term Calorie Restriction with Adequate Protein and Micronutrients on Thyroid Hormones

https://academic.oup.com/jcem/article/91/8/3232/2656790

10. Andreea Soare, Roberto Cangemi, Daniela Omodei, John O. Holloszy, and Luigi Fontana

Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117452/

11. Jill Waalen Joel N. Buxbaum

Is Older Colder or Colder Older? The Association of Age With Body Temperature in 18,630 Individuals

https://academic.oup.com/biomedgerontology/article/66A/5/487/571283

12. A cross-section analysis of FT3 age-related changes in a group of old and oldest-old subjects, including centenarians’ relatives, shows that a down-regulated thyroid function has a familial component and is related to longevity https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956534/

13. M. P. Rozing J. J. Houwing-Duistermaat P. E. Slagboom M. Beekman M. Frölich A. J. M. de Craen R. G. J. Westendorp D. van Heemst

Familial Longevity Is Associated with Decreased Thyroid Function

https://academic.oup.com/jcem/article/95/11/4979/2835245

14. Can Enhanced Autophagy Be Associated with Human Longevity? Serum Levels of the Autophagy Biomarker Beclin-1 Are Increased in Healthy Centenarians. https://www.liebertpub.com/doi/10.1089/rej.2014.1607

15. Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians.

https://www.ncbi.nlm.nih.gov/m/pubmed/30352807/