Category Archives: Diet

Insight 10-Best Longevity diet = Mediterranean Diet

Diet, Individual controls aging,

Best diet for longevity

I previously discussed in Insight 8 that severe caloric restriction retards the onset of many diseases and increases longevity in animal models of aging (including the monkey).  I subsequently presented the status of the future caloric-mimetic drugs. These drugs are predicted to offer the same benefits (health and longevity) of caloric restriction minus the pain of caloric restriction (Insight 9).  However, in the interim until the advent of efficacious caloric-mimetic drugs, the question remains as to what is the best diet for longevity building.  The best answer to date is the Mediterranean diet.  It is the diet with the most convincing scientific support.  Most importantly, adherence to this diet is associated with a decrease in the incidence of cardiovascular disease, the major cause of death in our society.  As a result, disease reduction indirectly increases lifespan.  

Components of the Mediterranean Diet

The Mediterranean diet entails consumption of whole grains, legumes, fruits, vegetables, nuts, fish and olive oil, wine in moderation, and a low-moderate intake of meat, dairy products, processed foods and sweets (Vitale et al., 2018).  This ~2000 calorie/day diet derives more calories from plant based foods than from meat based foods and fat consumption is largely from mono- and polyunsaturated fats.  More details are presented in the adjacent table.  This table is the result of an extensive systemic review (59 studies) of the health effects of the Mediterranean diet (D’Alessandro et al., 2019).  The authors were able to assess the effect of each food group on disease prevention. From that, they developed the frequency and serving size of the components of this diet needed to achieve these health benefits.      

Summarized from D’Alessandro et al., 2019

Origin of the Mediterranean diet

A study called Seven Countries Study of Cardiovascular Diseases began in the late 1950s and continued for some 50 years.  This seminal study tracked over 12,000 middle-aged men in North America, Northern Europe, and Southern Europe. It correlated dietary patterns with the incidence and mortality rates for coronary heart disease (CHD) and overall mortality (Menotti  and Puddu, 2015).  The striking findings showed that the incidence of CHD, other cardiovascular diseases and overall mortality was lower in southern Europe (Mediterranean countries and Japan) than anywhere else.  This improved health and longevity significantly correlated with decreased saturated fat consumption (low levels of serum cholesterol) and increased calorie intake from plant foods relative to animal meats.  In other words, this became known as the Mediterranean diet.

Proven benefits of the Mediterranean diet

There are numerous observational studies and clinical trials on the effects of adherence to the Mediterranean diet to health outcomes.  To make sense of the wealth of data, meta-analysis combines results from the  most rigorous studies to yield what are considered substantiated and valid conclusions.  The most recent of these meta analysis (Sofi et al., 2008; Dinu et al., 2018) evaluated 13 observational studies and 16 randomized clinical trials with regard to 37 different health outcomes. The results show adherence to the Mediterranean diet yields lower mortality for:

  1. Cardiovascular disease, Coronary heart disease, Heart attack
  2. Neurodegenerative diseases
  3. Cancers
  4. Diabetes
  5. All causes

However, there are limitations to studies assessing dietary patterns since they rely on validation of dietary questionnaires.  Hence, the need for the meta analysis that shows with a high degree of confidence that adherence to the Mediterranean diet compared to a non Mediterranean diet e.g. western diet, consistently yields valuable health benefits. 

Future – how the Mediterranean diet works

Several studies have endeavored to probe the underlying mechanism(s) of the Mediterranean diet on health benefits.  As a result, it has been shown, albeit in small studies, that the adherence to the Mediterranean diet for 6 months to one year lowers blood pressure (Davis et al., 2017; Jennings et al., 2019), improves dynamic blood flow (Davis et al., 2017), decreases proinflammatory mediators (Dyer et al., 2017) and reduces arterial stiffness (Jennings et al., 2019).

Other diets e.g. Okinawa, DASH and Portfolio will be discussed in my next blog.

ReferencesDownload

Insight 9 – Replacement for caloric restriction

Diet, Individual controls aging, , , , ,

The caloric restriction mimetic – better than starvation

Caloric restriction (CR) is severe reduction in calorie intake.  It must be maintained for an extended period of time and be supplemented with essential nutrients.  It is often called “starvation without malnutrition”.  However, the reward of this difficult protocol is exceptional:  a longer and healthier lifespan (see Insight 8).  The obvious problem is that, unlike animals under investigative experimentation, humans cannot endure this degree of starvation for any significant length of time.  Thus the search for drugs that would produce the same benefits of CR without the pain of eating less.  These drugs are termed caloric restriction mimetics (CRMs).

The caloric restriction mimetic – 3 of interest:

1.  Sirtuin (SIRT)-activating compounds e.g. resveratrol

2.  Metformin

3.  Rapamycin

Sirtuin-activating compounds

Sirtuin-activating compounds stimulate specific genes (SIRTs) to produce proteins termed sirtuins.  Sirtuins (chemically defined as NAD histone deacylases), in turn, act to change cell metabolism for the better.  Sirtuins perform several significant functions.  Some of these are 1) reduction of inflammation through depression of the master gene (NF-κβ), 2) greater recycling of damaged proteins, and  3) improvement of insulin signaling.  Together these activities and many more contribute to a healthier life.

How are sirtuins related to CR?  In animal models of aging, CR activates the genes (SIRT family) that produce the sirtuins and consequently, the level  of sirtuins increases with CR.  Secondly, in genetic experiments which insert an extra SIRT gene into an experimental animal, the level of sirtuins increases and beneficial changes comparable to CR occur.  So chemicals that elevate the level of sirtuins should produce the same beneficial effects of CR.  Thus the development of sirtuin-activating compounds.

Resveratrol – role in caloric restriction

A notable sirtuin-activating compound is resveratrol, originally isolated  from red wine and when concentrated (1000 fold), resveratrol produces effects similar to CR such as an increase in maximal lifespan, reduced inflammation, and delay in disease onset.   Unfortunately, resveratrol is poorly absorbed by the gastrointestinal tract and so analogs with greater bioavailability have been developed.  Analogues have been evaluated in rodents and in man.  Generally in rodents, improved health benefits e.g. delay in disease onset have been observed. 

In man, clinical trials assessing one particular analogue, SRT2104, for therapy of psoriasis, ulcerative colitis, sepsis, and vascular dysfunction in smokers and type 2 diabetes (T2D) have been completed.  Thus far only results for the effect of oral SRT2104 on psoriasis have been published and showed reasonable safety and a modest reduction of disease pathology.  This was a small study (40 patients, 84 days of treatment) that warrants additional evaluation according to Kreuger et al., (2015).   As published results become available, updates will be provided.

Metformin

Metformin is a caloric restriction mimetic.  It is also an FDA approved drug for treatment of T2D. Much is known on how it works to block production of glucose by the liver.  A striking finding was that patients taking metformin for T2D lived longer than those without diabetes and of course not taking metformin.

When used in animals, metformin delays the onset of disease and in some animal models of aging, it extends the lifespan.   It acts in multiple ways to alter nutrient sensing and improve cellular activities related to gene function, recycling of damaged cell components and slowing age-related changes.  These changes mirror those produced by lifelong CR. 

To further understand the caloric restriction mimetic effects of metformin, the FDA (2016) granted approval of its use in a clinical trial to determine whether metformin will delay the onset of disease.  The trial named Targeting Aging with Metformin (TAME) trial will enroll 3000 patients (65-79 years of age) and follow them for 6 years to determine whether metformin delays the onset of major age-related diseases e.g. heart disease, cancer and dementia (https://www.afar.org/tame-trial).  The results are eagerly awaited.

Rapamycin

Rapamycin is an antibiotic and potent immunosuppressant drug to prevent organ rejection.  In animal models of aging including the mouse, treatment with rapamycin extends the lifespan and delays the onset of age-related diseases.  Thus rapamycin is a caloric restriction mimetic.  It acts by inhibiting an important nutrient sensor called mTOR.  This nutrient sensor is activated by insulin.  Therefore, in the presence of rapamycin,  insulin-mediated metabolic effects are significantly reduced. 

Chronic use of rapamycin in man is limited to very low doses due to untoward side effects. However, the Dog Aging Project completed a placebo-controlled trial with 24 healthy companion dogs treated with a low dose of rapamycin for 10 weeks.  The drug is safe and improves cardiac function as determined by an echocardiogram before and after treatment.  Funded by a grant from National Institute of Aging and private donors, the next experiment will enroll a larger number of companion dogs and seek to determine whether aging can be delayed in dogs with this CRM.  

The objective of the Dog Aging Project (dogagingproject.org) is to understand aging in dogs and translate the information to humans.  This is based on observations that humans and dogs share the same environment, they have many biological mechanisms in common and also develop many of the same diseases.  Insights into dog aging should contribute to understanding human aging.

Comparison of diet and mimetics

Common Pathway

The schematic illustrates one known pathway altered by CRMs.  As with CR, these drugs also target the nutrient sensor termed mTOR (mammalian target of rapamycin).  This sensor was uncovered in part with studies using rapamycin.  mTOR is a key protein that affects many other essential pathways in the cell.  When its activity is reduced, more efficient metabolism ensues, recycling is enhanced and inflammation is minimized. The future caloric restriction mimetic will potentially replace dietary caloric restriction.

References of interest

1.  Krueger JG, Suarez-Farinas M, Cueto I et al.  A randomized, placebo-controlled study of SRT2104, s SIRT1 activator in patients with moderate to severe psoriasis. PLoS ONE 10(11): e0142081

2.  Kulkarni AS, Gubbi S, Barzilai N.  Benefits of metformin in attenuating the hallmarks of aging.  Cell Metab 32:  15-30, 2020.

3.  Urfer SR, Kaeberlein TL, Mailheau S.  A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle aged companion dogs.  GeroScience 39:117–127, 2017.

Insight 8-Caloric Restriction

Diet, Individual controls aging, , , ,

Importance of caloric restriction (CR)

Previous blogs have focused on specific organ-systems such as skeletal muscle (Insights 2-5) and the brain (Insights 6,7).  Insight 8 describes a proven but difficult path to longevity that impacts ALL organ-systems. This path is one of rigorous caloric restriction. Thus caloric restriction promotes longevity. It is a longevity builder.

Low calorie foods

Not quite a century ago, a Cornell University researcher, Clive McKay who was studying nutrition in rats, reported that rats who ate 30% less calories than those with free access to food, appeared healthier and lived longer than the controls with unlimited access to food.  All rats consumed adequate intake of vitamins, minerals, essential amino acids and fats throughout the study.

Significance of caloric restriction

First, CR is a repeatable experiment. It has been replicated in many different animal models that include yeast, round worms, fruit flies, mice, dogs, and monkeys.  In all studies, CR restriction of 25-30 or more percent produces a significant extension of lifespan with positive effects on a variety of organ-systems.  

Secondly, the CR studies revealed at least one important mechanism of aging. Thus scientists now know that lifespan (at least from yeast to monkey) can be successfully lengthened with reduction in consumption of calories.

Thirdly, CR opened the door to the identification of drug “mimetics” of CR. These new drugs would work like CR but, importantly, bypass the known difficulty for humans to eat less.

Known benefits of caloric restriction

CR produces many benefits in addition to an increase in lifespan.  This has been studied in depth in rodents and monkeys.  Generally, compared to control animals, CR animals exhibit

   (a) a delay in the occurrence of major diseases,

   (b) a delay in the decline in muscle mass,

   (c) a delay in the decline of the immune system, and

   (d) a delay in the decline in some DNA repair mechanisms (protecting cells from random damage). 

Body temperature may decline slightly but overall physical activity in CR animals compared to controls is normal or slightly increased.  Significantly, and considered the driving force behind the above beneficial changes is a shift in how sugars are metabolized.  CR animals utilize new pathways that  reduce the requirement for insulin, a known pro-aging factor.

Results of CR in monkeys

One of the most important studies on CR are the ongoing ones using Rhesus monkeys at the National Institutes of Aging (NIA) and Wisconsin University (Colman et al., 2014; Mattison et al., 2017).  Monkeys began a 30 percent reduction in calories when they were adults.  After 20 years, the number of CR-treated monkeys exceeded that of the controls (survival in the CR group was 80% versus 50% in the control group).  Other benefits, to name a few, include:

   (a) a delay in age-related pathologies such as diabetes, cardiovascular disease, cancer and brain-related disorders;

   (b)  lower blood pressure, heart rate, fasting blood glucose and a favorable lipid profile (low LDL and triglycerides and high HDL);

   (c)  normal levels of testosterone and estrogen, maintenance of “youthful” levels of melatonin (sleep agent) and dihydroepiandrosterone (DHEA popular supplement considered the precursor to hormonal steroids such as estrogen and testosterone);

   (d) maintenance of immune system function (lower levels of inflammatory mediators and higher levels of anti-inflammatory agents); and

   (e) decreased oxidative damage to muscles and decreased onset of sarcopenia (see Insight 2). 

Application of caloric restriction to man

The first study in man was an observational, retrospective and case-controlled study of 18 volunteers (average age ~ 50 years) in self-imposed CR for 3-15 years paired with 18 healthy same age, sex, but eating a western diet (high fats and carbohydrates).  Compared to those eating the western diet, CR individuals had a lower body mass index, less body fat, more lean muscle mass, lower levels of LDL, triglycerides and fasting glucose and insulin and higher HDL and lower levels of a key inflammatory mediator, C-reactive protein (Fontana et al., 2004).

NIA sponsored the clinical trial, CALERIE = (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) Study  which has completed several small (~50 volunteers) phase I trials of 6 months to 1 year duration and a larger (218 volunteers) phase II trial that lasted 2 years.  In both phases the target caloric reduction was a minimum of 25% but in phase I, individuals achieved a 10-17% caloric reduction and in the longer trial, only a 12% caloric reduction was achieved.  Even with this modest CR, there were positive changes such as decrease in fasting glucose, decrease in inflammatory makers, improved cell function and decrease in cardiovascular risk factors.  However, the CR reduction was too modest and phase II too short to achieve the milestones evident in the monkey studies.

Caloric restriction – next steps

The difficulty for humans to adhere to a 30% reduction in calories has ushered in interest in developing drugs to “mimic” CR.  As the thinking goes, in the future, individuals will be able to take a drug that mimics CR and also be able to eat whatever is desired.  Three candidate drugs have been proposed:

a) metformin

b) rapamycin

c) sirtuins

A discussion of these 3 compound will be the topic of my next blog.

References                          

Fontana et al.,  Proc Natl Acad Sci USA 101:  6659-63, 2004.

Colman et al., Nat Commun 5:  3557, 2014

Mattison et al., Nat Commun. 8:  14063, 2017.