A large proportion of present research into the mechanisms of aging seeks the underlying reasons that link good lifestyle choices with greater life expectancy and lower incidence of age-related disease. When considered in the grand scheme of things, looking towards a future of rejuvenation and life spans ultimately extended by centuries and more, this is a fairly parochial concern: natural variations in longevity will cease to be important shortly after the clinical availability of the first generation of rejuvenation therapies based on the SENS research portfolio. Nonetheless, most investigative research is focused on what takes place today, on the way in which the current operation of metabolism determines the current pace of aging. The open access paper linked below is a good example of the type, focused on glucose metabolism, dysregulated in those who become overweight and diabetic, and the anti-diabetic drug acarbose. In the sense that today's large population of obese and diabetic individuals are a natural experiment in the human biochemistry of aging, members of the research community would like to learn what they can from this data.
Most of the readers here will know that type 2 diabetes is a lifestyle condition for the vast majority of patients, arising due to the effects of excess visceral fat tissue. This abnormal metabolic state in effect accelerates the damage of aging, through mechanisms such as increased chronic inflammation, but also others that stem from the malfunctioning glucose metabolism that diabetic patients exhibit. Researchers have used diabetes in animal models as a substitute for the aging process on a routine basis for decades, as the progression is more rapid and thus the studies are less costly in time and money. Diabetic patients have a shorter life expectancy and greater incidence of age-related disease than their healthy peers. This is also true, to a lesser degree, of those with lower levels of metabolic disorder and visceral fat, people who are on the way to full-blown diabetes but not there yet.
There are a range of drugs that interact with the dysfunctional diabetic metabolism to make matters less terrible, but no substitute for just losing the weight - low-calorie diets work pretty well even in later stage type 2 diabetes, and it is quite amazing that so few people actually undertake this course of action given the reliably positive outcomes. Among these drugs, acarbose is interesting because it has been shown to modestly extend life in normal mice. The effect of the drug is to inhibit uptake of carbohydrates from the diet, and thus reduce the delivery of new glucose into the workings of metabolism. That result suggests that we could all benefit to some degree from a lower intake of complex carbohydrates, such as the readily available sugar that is everywhere these days, not just the overweight and the diabetic. The authors of the paper here go into some detail while considering the mechanisms involved, though note that, like many researchers, they are unwilling to step beyond compression of morbidity within the existing human life span as a viable goal to aim for.
Aging is considered the largest risk factor for a variety of chronic and metabolic diseases. Unlike many risk factors (i.e., smoking, diet, weight gain), aging, by strict definition as the act of growing old, has not historically been considered to be modifiable. Aging and risk of disease development are so well intertwined that skepticism surrounding the idea of longevity extension persists, as a longer lifespan is considered by some as simply a prolonged opportunity to develop additional age-related diseases. Despite this concern, contemporary pursuit of methods to increase lifespan and healthspan through the process of slowing the accumulation of age-related damage to cells and tissues continues. Conceivably, an intervention to extend lifespan and/or healthspan would act through slowing the fundamental aging process(es) rather than preventing a single disease. It is possible that interventions to slow the aging process may result in an individual experiencing an extension of healthspan without significant increases to lifespan, as it is currently unknown if maximal lifespan can be extended in humans. Therefore, an individual might experience a compressed window of morbidity by living the great majority or potentially the entirety of lifespan without developing the disorders now commonly associated with aging.
A common co-morbidity observed in aging is metabolic dysfunction. While metabolic (e.g., glucose and mitochondrial) dysfunction is frequently associated with aging, the causal relationship between aging and metabolic dysfunction remains to be fully understood. The risk relationships among age and metabolic associated diseases suggest some factors may be better primary targets for longevity interventions than others. For instance, curing cancer may not necessarily be expected to significantly affect the subsequent risk for type 2 diabetes (T2D) or cardiovascular disease. In contrast, cardiovascular disease and T2D are more widely recognized as possible contributors to neurological disease risk and when remediated, could reduce the risk of dementia and neurodegenerative disease. Considering the coordinate increase in risk for a number of chronic diseases with advancing age and given the unclear interrelationship between these diseases, a stronger case might be made for targeting glucoregulatory control to decrease disease risk and consequently improve longevity. In fact, T2D is a significant risk factor for most other age-related diseases. If glycemic control were successfully maintained with advanced chronological age, this might slow the aging process, potentially delaying or preventing the development of multiple age-related diseases, allowing an individual to live healthier for longer.
Exactly which cellular or molecular mechanism(s) is primarily responsible for the associations of elevated glucose with chronic disease risks is not fully understood. Proposed causative mechanisms leading to accelerated aging include direct methods such as amplified and inappropriate glycosylation events, along with the production of advanced glycation end products that damage cellular functions from DNA repair to structural integrity and indirect contribution to the production of reactive oxygen species. Alternatively, maintenance of glycemic control may function as a biomarker of health maintenance from the cell to the organismal level. As such, one might expect a range of interventions targeting diverse mechanisms could share this glucoregulatory phenotype, resulting from some combination of maintained integrity of the cell, organelles, hormonal signaling or other factors coordinating metabolism and ultimately aging across the organism. Thus by indirect means, changes in glucose levels could significantly impact transcriptional programs or hormonal signaling to coordinately regulate processes currently known (or unknown) to influence the aging process (e.g., mitochondrial function, autophagy).
Glucose dysregulation, measured as either hypoglycemia or hyperglycemia, can result from problems along the entire glucose uptake, production, and metabolism spectrum. Hyperglycemia is commonly associated with advancing age and can occur as a result of decreasing insulin release in response to glucose and/or increased insulin resistance by tissues. Recent surveys of the adult population in the United States suggest that ≥50% of individuals over 45 years of age have T2D or prediabetes. This prevalence is greater with increasing age, with ∼80% of adults 65 or older showing glucose dysregulation. Thus, impaired glycemic control is approaching epidemic proportions both in the U.S. and throughout the world. Although the source of the metabolic imbalance driving glucose dysregulation may have multiple contributors, a surfeit of energy intake with increasing body weight and BMI are proposed to contribute.
One of the most direct methods of maintaining glucose homeostasis is through diet/nutritional interventions. Paramount among these is the dietary restriction (DR) or calorie restriction (CR) paradigm. Despite these reported health benefits, life-long dietary restriction in humans remains challenging given the current state of modern society in developed countries that has shifted from a limited food supply a century ago to nutritional excess today. Therefore, the identification of interventions that promote health and longevity independent of obligatory food intake reductions has been proposed as an alternative means to "mimic" the physiologic benefits of CR and reap health and longevity gains - a hypothetical class of compounds termed calorie restriction mimetics (CRMs).
The similarities between glucose dysregulation in aging and glucose dysregulation with T2D have led to the hypothesis that an effective CRM could be found by targeting glucoregulatory control. If an intervention is able to improve glucose regulation to treat or prevent T2D, it may prevent development of glucose dysregulation commonly observed with aging. The most well-known T2D drug that has been tested as a CRM is metformin. Metformin is reported to act through multiple pathways; however, the best-characterized pathway is through the activation of the cellular energy regulatory sensor AMP-activated protein kinase (AMPK). More recent pre-clinical work has highlighted another class of diabetic control agents that work upstream of insulin (and presumably metformin-related targets) while providing health and longevity benefits in lab models - namely the α-glucosidase inhibitor acarbose (ACA). When consumed with a complex carbohydrate-containing meal, ACA acts as a competitive inhibitor to carbohydrate breakdown along the brush border of the small intestine, resulting in reduced enzymatic degradation and absorption of glucose from complex carbohydrates. This inhibitor effect lowers the post-prandial blood glucose elevation in a dose-dependent manner.
Studies with non-diseased humans and rodents, as well as diabetic individuals, have described beneficial metabolic effects, most notably as reduced post-prandial blood glucose excursions with ACA. Insulin sensitivity is slightly improved with ACA, though post-prandial insulin levels do not show a consistent significant decrease. While the molecular, inhibitory action of ACA is well-detailed, fewer studies have attempted to explore the effect ACA has on specific nutrient retention from the diet and specifically if the weight loss sometimes reported with ACA administration is the result of reduced overall energy retention from the diet. Given the important roles of insulin signaling and IGF1 in body weight homeostasis and longevity, the benefits of ACA are more likely a result of the slowed uptake of sugars from the diet, resulting in lower post-prandial glucose excursions and moderated insulin responses. Considered as a whole, even in the absence of overt disease, these data suggest targeting glucoregulatory maintenance by acarbose or other means may be a viable nutritional target for maintaining health and delaying aging.