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

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.