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Fasting-Mimicking Diet

iStock-1421136889Nature Communications has published results of a secondary analysis of a previously published clinical trial, examining the effects of a fasting-mimicking diet (FMD) on a number of cardiometabolic risk factors as well as a calculation of “biological age” among study participants. The FMD used in this clinical trial was characterized as plant-based and hypocaloric (with proprietary foods provided), followed for only 5 days and then by 25 days of participants’ typical diet, thus completing 1 cycle (3 consecutive cycles were completed, 3 months in total). Additionally, 32 of the 43 members of the control group crossed over to the FMD diet after 3 months of their typical diets, and completed 3 months of an FMD, allowing for intraindividual comparisons.

The proprietary FMD diet provides approximately 1100 kcals on day 1, and 717 kcals on days 2-5 of each cycle, roughly 10% of which is protein and the remaining 90% is divided nearly evenly by carbohydrates and fat. FMD clinical trials generally have shown metabolic improvements for a variety of clinical outcomes, including disease-free participants, people with diabetes, and people with cancer. This secondary analysis utilized data from a clinical trial with 100 healthy participants published in Science Translational Medicine, which documented improvements in multiple metabolic variables with the FMD compared to the control diet, including body weight, trunk and total body fat, blood pressure, and IGF-1.

The authors of this recent analysis concluded that the FMD was associated with a median reduction in 2.5 years over the study period, while the control group did not see any change in biological age (a non-significant increase of 0.78 years). Additionally, it appeared that participants with the highest biological age at baseline had the largest improvements, though it’s worth noting that approximately 1/5 of those following the FMD experienced a slight increase in biological age, compared to 3/5 in the control group. Both groups had a slightly lower biological age than their chronological age at baseline, suggesting a healthier-than-average population.

This analysis utilized a definition of biological age developed previously that out-predicted mortality compared to chronological age in an NHANES dataset, one which relies entirely on conventional laboratory results. The clinical labs used in this calculation included albumin, alkaline phosphatase, creatinine (serum), C-reactive protein (CRP), glycated hemoglobin (Hba1c), systolic blood pressure, and total cholesterol (and utilized the Klemera and Doubal algorithm, 7 variable). Many different assessments of biological age have been proposed, including scores based on the epigenome, the transcriptome, the proteome, etc., and none are universally accepted. Nonetheless, this calculation of biological age was found to be more predictive than chronological age for determining remaining life expectancy, is of low cost, and similar models (with 18 variables) have been associated with aging even among adults before mid-life, and thus not limited to only older adults.

The authors also performed a number of calculations based on their theoretical models, extrapolating the potential benefit if 3 cycles (3 months) of FMD were completed on an annual basis. For example, completing 3 cycles of FMD annually starting at 50 years of age (compared to zero cycles of FMD) could plausibly increase the median life expectancy at age 70 by 5 years. In other words, those following an FMD annually (starting at age 50) would have a life expectancy of 88.3 years, versus a life expectancy of 83.2 years among people following a standard diet. It is also likely that they would have lower rates of age-specific diseases, and potentially a longer health span, e.g., the period of life with greater quality of life and function.

It should be pointed out that much of this is speculation, however encouraging the early data. The clinical trials were quite small, the participants appeared healthier and may be otherwise advantaged compared to the average person (socioeconomic, behavioral, overly enthusiastic, etc.), we don’t have long-term compliance data for the FMD yet, and this study evaluates biomarkers, not hard outcomes, and the composite scores may not necessarily translate to actual benefit.

Nonetheless, the cardiometabolic improvements, including positive changes in body composition (measured by dual-energy x-ray absorptiometry (DEXA)), should highlight the potential to slow the aging process. Experimental data consistently seems to indicate that a reduction in calories (and potentially time spent eating) is associated with greater health and longevity, at least in animal trials. Periods of fasting may allow for the targeted destruction of dysfunctional cells, and it is plausible that it is the survival of these senescent and inflammatory cells (e.g., immunosenescence and its associated “inflammaging”) that drive many age-related disease processes. Thus, a form of fasting that may be more sustainable over time, yet is sufficient to promote autophagy, may strike the right balance between fasting and real-world compliance. Additionally, the limited period of low-protein intake may minimize any potential losses in lean tissues (e.g., muscle mass) that are especially concerning in middle-aged and older adults, and the use of plant protein may mitigate some of the harm associated with animal-based protein (e.g., greater mortality and cancer risk) that has been cited in observational studies. Long-term, well-validated, and well-powered investigations into the FMD are eagerly anticipated.

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