Intermittent Fasting Shown to Effectively Treat Type 2 Diabetes

Intermittent Fasting Shown to Effectively Treat Type 2 Diabetes

A recent study published in The Journal of Clinical Endocrinology & Metabolism has shown a dietary approach that might reverse type 2 diabetes for millions of people currently suffering from this disease. Moreover, this approach costs nothing and does not require the use of pharmaceutical therapies.

Type 2 Diabetes

Type 2 diabetes is a chronic condition that occurs when the body becomes resistant to the effects of insulin, a hormone that regulates blood sugar levels, or when the pancreas is unable to produce enough insulin to maintain normal blood sugar levels. It is the most common form of diabetes, accounting for approximately 90-95% of all cases.

Type 2 diabetes can have serious health consequences if left untreated, provoking a range of complications including heart disease, stroke, kidney disease, blindness, nerve damage, and amputation. People with type 2 diabetes are also at an increased risk of developing high blood pressure and high cholesterol, which can further increase the risk of these complications. It is important for individuals with type 2 diabetes to carefully manage their blood sugar levels and make lifestyle changes, such as eating a healthy diet and getting regular exercise, to prevent or delay the onset of these complications.

Historically, the costs of diabetes have been a major burden for both individuals and society. In the United States, the total direct and indirect costs of diabetes were estimated to be $327 billion in 2017; this includes the cost of medical care, as well as lost productivity and reduced quality of life, and is expected to reach $532 billion by 2030. The projected cost of diabetes is of concern as the prevalence of the disease is expected to increase in the coming years. It is estimated that the number of people with diabetes will reach 439 million by 2030, and 592 million by 2035. This increase is largely due to the aging population and the increasing prevalence of obesity, which is a major risk factor for type 2 diabetes. The rising cost of diabetes will have significant implications for both individuals and society, and efforts to prevent and manage the disease are important in order to reduce these costs.

Intermittent Fasting

Intermittent fasting is an eating pattern that involves cycling between periods of eating and fasting. It is not a diet in the traditional sense, as it does not specify which foods to eat, but rather when to eat.

Intermittent fasting has a long history, with roots in various social, cultural, and religious practices. In many cultures, fasting has been a common practice for spiritual or religious reasons, with people abstaining from food and drink for certain periods of time as a way to purify the body and mind or to show devotion to a deity. This approach has also been used as a way to improve health and wellbeing, with some traditional medical systems, such as Ayurveda in India and traditional Chinese medicine, recommending fasting as a way to cleanse the body and promote healing.

Clinically speaking, intermittent fasting has been shown to have numerous health benefits, including weight loss, improved insulin sensitivity, reduced inflammation, and improved heart health. It may also have benefits for brain health and may even help to reduce the risk of certain diseases, such as cancer and Alzheimer’s disease. However, more research is needed to fully understand the long-term effects of intermittent fasting and to determine the extent of its benefits and the best approach for individuals.

Study Results

This recent study examined the effectiveness of Chinese Medical Nutrition Therapy (CMNT), an intermittent fasting diet, in achieving diabetes remission. Participants having a normal to overweight BMI between the ages of 38 and 72 who had been living with type 2 diabetes for 1 to 11 years and previously requiring the use of insulin or other antidiabetic therapies were randomly assigned to either the CMNT (intermittent fasting) or control group. The study intended to examine the effect of CMNT relative to diabetes remission as defined by the maintenance of a consistent HbA1c level—a well-established measure of glucose metabolism and indicator of type 2 diabetes—below 48 mmol/mol for at least three months after discontinuing all antidiabetic medications. In addition to HbA1c level, fasting blood glucose level, blood pressure, body weight, and quality of life were also observed.

Participants were assessed after 3 months of intervention and at 3 months post-intervention. In addition, the researchers conducted a 12-month follow-up to see if remission was sustained.

In the CMNT group, 47.2% of participants achieved diabetes remission after completing the 3-month intervention and 3-month follow-up. In contrast, only 2.8% of the control group achieved remission. The body weight of participants in the CMNT group was reduced by an average of 13.1 pounds, while the body weight of participants in the control group was reduced by an average of 0.6 pounds. During the 12-month follow-up period, 44.0% of participants in the CMNT group still maintained a state of diabetic remission.

Unsurprisingly, the study also found that participants with shorter diabetes duration, lower HbA1c levels, and fewer antidiabetic medications at baseline were more likely to achieve diabetes remission. In addition, the study found that the CMNT diet was associated with persistent improvements in HbA1c level, fasting blood glucose level, blood pressure, and quality of life.

This research indicates that an intermittent fasting dietary approach might offer a promising tool for the clinical management of type 2 diabetes. Further research is needed to understand its long-term sustainability and mechanisms of action.

A Modified Mediterranean Diet Reduces Unhealthy Visceral Fat

A Modified Mediterranean Diet Reduces Unhealthy Visceral Fat

The Mediterranean diet—high in nuts, olive oil, and vegetables with a moderately reduced but varied consumption of fish, meat, and dairy—has gained notoriety as an ideal diet for human health. Populations in regions from which the diet draws its name are protected against a variety of diseases, including diabetes and cardiovascular and metabolic diseases. The imparted health benefits are believed to be attributable to a variety of compounds in the diet’s plant-based components known as polyphenols. Recent work published in BMC Medicine has found that polyphenols likely contribute to the health benefits provided by the Mediterranean diet, and further enrichment of these compounds in the traditional Mediterranean diets reduces unhealthy visceral fat.

Visceral fat, the bad one

Not all fat is created equal. Fat depots in the body are characterized by their location and function. Subcutaneous fat, lying just below the skin, is considered to be relatively inert; however, visceral fat, located deep within the abdominal cavity, has been associated with an increased risk of cancer, cardiovascular disease, and type 2 diabetes.

Even in individuals at a healthy weight, dyslipidemia—a condition marked by disproportionally large amounts of visceral fat—can result in increased systemic inflammation through the secretion of hormones known as adipokines. This “hidden” fat, popularly referred to as TOFI (thin outside, fat inside), has complicated the use of percent body fat and body mass index (BMI) as reliable metrics for health.

Polyphenols

Polyphenols are a loosely categorized and diverse group of chemicals containing a phenol ring and commonly found in plants. Their consumption has for many years been associated with positive health outcomes. It is thought that this group of chemicals provides both antioxidant and anti-inflammatory benefits, aiding in the prevention of cardiovascular disease, type 2 diabetes, and hypertension; however, the effects of polyphenol consumption on obesity are not well known.

The traditional Mediterranean diet, containing a relatively high amount of plant food sources, is rich in polyphenols and has been shown to enhance the reduction of visceral fat when paired with moderate exercise. Recent trials have set out to determine if a further increase of polyphenols alone is sufficient in reducing the amount of visceral fat.

DIRECT-PLUS Trial

The 18-month Dietary Intervention Randomized Control Polyphenols Unprocessed (DIRECT-PLUS) trial examined the effects of a modified Mediterranean diet containing fewer red and processed meats and more polyphenols (green-MED diet). In order to attain high levels of polyphenols, the green-MED diet was supplemented with green tea and mankai duckweed (Wolffia globose), two plants rich in polyphenols and thought to provide health-related benefits.

When compared to both a diet formulated along healthy dietary guidelines and a traditional Mediterranean diet, the green-Med diet showed an improvement in adiposity through the reduction of visceral fat depots. Although both styles of Mediterranean diet provided some form of weight loss, the green-Med diet showed a reduction in visceral fat twice that of the traditional Mediterranean diet. In accordance with the reduction of visceral fat, the green-Med diet improved the profile of circulating lipids, improving both triglyceride and cholesterol levels.

Another fat depot found deep within the abdominal cavity, deep subcutaneous adipose tissue, was found to be equally reduced. This fat is structurally similar to the subcutaneous fat found beneath the skin but, much like visceral fat, the accumulation of this fat is associated with impaired glucose metabolism. The reduction of deep subcutaneous fat in the subjects fed a green-MED diet was, as expected, associated with improved markers of glucose metabolism.

Findings such as these support ever-growing evidence that achieving a healthy diet and healthy amounts of body fat are more nuanced than simply accounting for calories or body fat percentage. Food sources, especially plants, contain chemicals that seem to act directly on metabolic pathways similarly to the actions of pharmaceuticals. Understanding and utilizing dietary components such as phytochemicals can contribute to a dietary regimen optimized for human health.

2022 OFAS Report of Directors

2022 OFAS Report of Directors

As the year comes to a close, we at the Orentreich Foundation for the Advancement of Science (OFAS) wish to thank our friends around the globe for their continued support. To view our recently published 2022 Report of the Director, click here.

We hope you will consider investing in OFAS’s research efforts with a donation. With each day that passes, advancements are made toward the goal of extending healthy lifespan, and each day OFAS is able to be a part of this work because of friends like you.

Thank you for your part in making OFAS’s 2022 such a success!

Sincerely,

David S. Orentreich, MD, FAAD
Director

Cellular Reprogramming, a Viable Means of Lifespan Extension

Cellular Reprogramming, a Viable Means of Lifespan Extension

Age is the number one factor associated with the reduced function of multiple organ systems of almost every known organism. Attempts to efficiently and maximally extend lifespan would, therefore, require a systemic reduction to the rate of aging and improvement to the function of tissue in multiple organ systems. Research published in Aging Cell provides evidence that a single short interval of cellular reprogramming provides a robust and lasting systemic improvement to both the rate of aging and the function in numerous tissues, resulting in an extended lifespan.

Yamanaka Factors and Lifespan Extension

In 2007, Nobel Prize-winning biologist Shinya Yamanaka pioneered research developing a means to reprogram mature, differentiated cells back to stem cells. Forced expression of four proteins, known as Yamanaka factors, is capable of inducing a sort of “cellular amnesia”, resulting in a reversion to their original and more versatile or pluripotent state. Although induced pluripotency is capable of rejuvenating effects, the chronic long-term expression of these factors has been problematic in whole organisms, ultimately leading to cancer and premature death. However, as we reported earlier this year, periodic expression of Yamanaka factors over the lifetime of an organism was capable of reducing the rate of aging in a limited number of tissue systems in mice, and of altering a variety of physiological factors such that they were similar to those of younger animals, while avoiding carcinogenesis and premature death, demonstrating an approach increasing both health and longevity.

Furthermore, the recent work by Q. Alle et al, has shown that utilizing the same periodic approach—over a short period (2.5 weeks), as opposed to the continuous lifelong regime­—is sufficient to extend the lifespan of progeroid mice. These mice carry a genetic mutation resulting in a phenotype resembling advanced aging with concomitant degradation of multiple organ systems and severely shortened lifespans, making them ideal models for lifespan-extending interventional studies. In addition to the increased lifespan, tissues from multiple organ systems of mice subjected to a single transient expression period appear to be younger than untreated animals of the same chronological age.

Study Findings
Body Composition and Tissue Preservation

Advanced aging is commonly associated with significant muscle loss known as sarcopenia. Preservation of lean body mass is highly correlated with increases in both healthspan and lifespan. Strikingly, the individual short treatment early in life provides lasting maintenance of lean body mass, antagonizing muscle loss, as well as preventing the increased adiposity commonly associated with advancing age. Following this observed preservation of muscle, treated mice also demonstrated lasting improvement in muscular strength and endurance.

Similar to muscle loss, osteoporosis leads to a significant loss in bone density and is also highly correlated to age. Muscle and bone atrophy are critical factors driving the increased frailty­­ associated with advanced age. Transient early treatment conserved bone volume and thickness, and also maintained the quality of cartilaginous tissues. In addition to contributing to a reduction in frailty through skeletal muscular preservation, various organ systems demonstrated similar improvements: skin, lung, kidney, and spleen all showed improved structural integrity and amelioration of age-related deterioration.

Epigenetic Drift

Gene expression can be regulated in a variety of ways, one of which is through modifications to the chromatin structures that DNA is spooled around—a process known as methylation. These methylated sites are collectively referred to as epigenetic marks, and they add a layer of control to gene expression. Epigenetic drift, a loss of fidelity in the pattern of epigenetic marks, is highly correlated with biological age and is thought to be a mechanistic regulator of the aging phenotype. Interrogation of this epigenetic pattern can be used to determine the efficacy of an intervention’s ability to modulate rates of aging.

In this study, brief cellular reprogramming early in life results in a partial reduction of epigenetic drift and preservation of methylation patterns similar to those observed in younger tissues. Interestingly, the patterns of methylation that remain conserved with age are at sites with proximal genes involved in pathways known to alleviate age-related degradation.

Future Research

Yamanaka factors offer a potentially potent method of promoting longevity and sustaining health. Due to the nature of these interventions and their application being limited to genetically modified laboratory animals, translation to a clinical application will take substantial effort. Importantly, studies such as these demonstrate both the efficacy and safety necessary to justify further pursuits.

A Bunch of Grapes a Day Might Keep the Doctor Away

A Bunch of Grapes a Day Might Keep the Doctor Away

It is well established that nutrition is vitally important to maintain health and to promote longevity. In addition to the macronutrients a well-balanced diet provides, fruits and vegetables contain a variety of small molecules known as phytochemicals, which can act in a quasi-pharmaceutical manner affecting a multitude of biological pathways. The consumption of grapes has long been thought to impart health benefits, and numerous studies have attempted to uncover the phytochemicals responsible for this; however, the search for one or more specific molecules responsible for the putative benefits of dietary grapes has remained elusive. In light of this, Dave, et al., have focused their research efforts on the consumption of whole grapes. Their findings, reported in the journal Foods, provide evidence that dietary supplementation with grapes has the potential to improve the quality and duration of life.

To interrogate the potential health benefits of the entire range of phytochemicals found in grapes, researchers supplemented the diets of mice with a whole grape powder. The amounts added to the experimental diets of mice studied would equate to a 150 lb. person eating 40 to 45 grapes per day. Experimentally, the diet having the most profound benefit when supplemented with powdered grapes was a high-fat diet designed to replicate the Western diet, which is known to increase the risk of obesity, cardiovascular disease, cancer, and various metabolic disorders. Mice on this diet are subject to metabolic dysregulation, resulting in a lifespan reduction of roughly one-third and the onset of multiple pathologies, e.g., diabetes and non-alcoholic fatty liver disease (NAFLD).

NAFLD is increasingly prevalent in Western cultures and an ever-growing issue globally as more regions adopt a Western diet. It is characterized by an excess accumulation of fat in the liver, leading to cellular damage and impaired function and a dramatic increase in the risk of developing liver cancer. In this recent study, large amounts of powdered grapes added to a high-fat diet altered the expression of genes involving lipid metabolism in the liver and abrogated the development of NAFLD. It is thought that one or more compounds found in grapes elicit a change in hepatic lipid metabolism, preventing deleterious fat accumulation. Surprisingly, these findings seem specific to the liver, as mice supplemented with grape powder were heavier than their non-supplemented counterparts, likely due to the accumulation of fat in depots other than the liver. This is consistent with other findings, suggesting that the detriment of increased adiposity is dependent on the type of and region where fat is accrued.

In addition to the liver-specific benefits, mice on the grape-supplemented high-fat diet exhibited a significant extension of lifespan when compared to mice on a high-fat diet alone. It is unclear whether changes in liver metabolism and the prevention of NAFLD are responsible for ameliorating the shortened lifespan caused by chronic consumption of a high-fat diet or if additional mechanisms are responsible.

Interestingly, there is growing evidence that NAFLD is correlated with increases in the severity of Alzheimer’s disease and the risk of developing dementia. Furthermore, there is evidence of a potential shared mechanism underlying both NAFLD and Alzheimer’s disease. The authors do note observed changes in both gene expression and behavior of mice fed a grape-supplemented high-fat diet consistent with prolonged preservation of brain function and plan to pursue these findings further.

Key Feature of Ant Longevity Revealed

Key Feature of Ant Longevity Revealed

In an attempt to understand secrets of longevity, researchers are focusing on the peculiar lifespan of ants, specifically queen ants. Along with their close relatives bees, ants are eusocial insects characterized by highly organized social systems comprised of castes. In this cooperative system, each caste (i.e., worker, soldier, and queen) carries out specific functions in support of the colony. As much as the social functions in castes are varied and strictly regulated, so too are lifespans between castes. The typical lifespan of a worker ant is a modest 1 to 2 years; queen ants, however, can live up to 30 times longer. As a result, a significant amount of research has been devoted to unraveling the mechanisms driving this feature. Yan, et al.,  report in Science that modulation of the insulin/IGF-1 signaling (IIS) pathway, shown to be crucial to many pro-longevity interventions, is responsible for extreme lifespan extension in queen ants.

Interventions that extend lifespan are numerous, utilizing dietary models (e.g., calorie and methionine restriction), genetic modifications (e.g., the Ames dwarf mouse), and pharmaceutical therapies (e.g., metformin) to achieve these benefits. Central to these approaches is the targeting of the ancient and highly conserved IIS pathway, which promotes survival when conditions are less than ideal for successful reproduction. IIS is acutely responsive to environmental nutrient status, and during periods of abundance, insulin and IGF-1 levels are elevated, initiating a cascade of changes allowing for maximal growth and reproduction. However, in the event an organism finds itself in an environment where nutrients are limited, IGF-1 is decreased and pro-growth pathways are inactivated in favor of mechanisms for maintenance and survival, e.g. autophagy, lipolysis, and ketosis. Consequently, animals that grow quickly and reproduce abundantly tend to have shorter lifespans; conversely, animals with impaired growth and reproductive faculties tend to have longer lifespans. As a result, many IGF-1 lowering, pro-longevity interventions have the added effects of reduced organism size and impaired reproduction.

Queen ants grow twice as large as workers and are solely responsible for colony reproduction, committing them to a perpetual state of egg production. To maintain this reproductive state, queens must consume an abundant amount of food. As a result, insulin and IGF-1 levels are chronically high and the IIS pathway activates a continual pro-growth signaling cascade, inhibiting pro-longevity maintenance processes. In most organisms, such a state would lead to a significantly reduced lifespan; however, queen ants live around thirty times longer than worker caste ants, despite nearly identical genetic backgrounds.

In order to understand the mechanisms underlying the paradoxical nature of this phenomenon, researchers examined the fat bodies of these long-lived queens. Fat bodies in ants are equivalent to mammalian livers, which are subject to the many changes instigated by insulin and IGF-1 signaling. Their findings revealed a surprising change in the pro-longevity protein FOXO. Typically, increased nutrient consumption results in elevated levels of insulin and the activation of the protein AKT. AKT in turn acts on FOXO by preventing its translocation into the nucleus; however, long-lived ants in this study were shown to have increased levels of FOXO localized to the nucleus, despite high levels of insulin. Upon localization to the nucleus, FOXO is then responsible for regulating genes that promote cellular maintenance and increased longevity. It was shown that elevated levels of the protein Imp-L2 allowed AKT levels to remain low regardless of high insulin levels. In the presence of increased insulin, Imp-L2 secreted from the ovaries is thought to block insulin receptors on the surface of cells in fat bodies, preventing the activation of AKT and allowing FOXO to activate pro-longevity genes within the nucleus.

This unorthodox control of the IIS pathway in queen ants could potentially lead to the development of novel therapies to treat age-related diseases in a manner that avoids the typical trade-offs of impaired growth and reproduction. Therapies capable of simultaneously promoting growth and maintenance could prove to be invaluable in aging populations, which are more prone to increased frailty and diseases of wasting.