The fountain of youth. Books have been written about it, movies have been made about it, and billion-dollar industries have been built around it. Cosmetics and personal care items, exercise contraptions and slickly marketed “superfoods” all promise to deliver “anti-aging” effects. Biohackers jump on the latest diet and lifestyle trends related to longevity, hoping to eek out a few more years of existence. But is there really some merit to any of this, or is it mostly wishful thinking? Recent research from the University of Miami opens new avenues for exploration regarding human aging.
While some people age gracefully, physically and mentally, and with all their cognitive faculties intact, these enviable specimens seem to be in the minority. For a larger portion of the population, healthspan decreases as lifespan increases—that is, as we age, we experience debility and decrepitude at a faster rate. A study published last month in Aging Cell, called “Longevity‐related molecular pathways are subject to midlife ‘switch’ in humans,” has uncovered information as to why this may happen. The findings are interesting because the research was conducted in human cells, whereas the majority of longevity research has been conducted in yeast cells, fruit flies, mice, worms and other short-lived or lower-order organisms.
Researchers found that the human brain and skeletal muscle cells studied had an endogenous “program” that contributes to regulating the aging process. Protective mechanisms are in place during the earlier part of life, but according to study co-author Claes Wahlestedt, MD, PhD, “humans appear to stop using these pathways from about 50 years of age onward. Therefore, how long and how ‘hard’ each person regulates these pathways may influence human lifespan.” Dr. Wahlestedt noted that the most validated “anti-aging” programs uncovered in lower organisms are indeed active in humans, but for unknown reasons, something puts the brakes on these in the sixth decade of life.
The intersection of lifespan and healthspan may be related to “nature versus nurture” or genetics versus lifestyle and environment. Everyone knows someone who smoked, enjoyed alcohol a bit too much, partied hard, and died at an old age in relatively good health. And we also know people who ate well, exercised, went out of their way to prioritize their health, yet developed an illness and died young despite their efforts to do the opposite. There may well be a genetic component to this—long and healthy lifespans often run in families—so it’s not possible to control all aspects of aging—unless you can pick better parents! But the study findings suggest we might have some control.
The Miami study found that as much as two-thirds of molecular aging in humans is explained by the mTOR protein complex (mammalian target of rapamycin) and by production of mitochondrial reactive oxygen species. mTOR is a key regulator of numerous processes involved in metabolism and aging, including cell growth and proliferation, autophagy and mitochondrial biogenesis. Chronic activation of mTOR may inhibit mitochondrial biogenesis and autophagy, potentially contributing to the progression of cancer and type 2 diabetes. Reactive oxygen species can cause chain reactions of damage to structural cellular and mitochondrial lipids and proteins, potentially accelerating the aging process. People are only as young as their mitochondria.
mTOR is a “nutrient sensor.” It’s “the master regulator of a cell’s growth and metabolic state in response to nutrients, growth factors and many extracellular cues.” It is upregulated by consumption of proteins and carbohydrates (especially simple sugars), so we can think of it as signaling that the body is in a “fed” state. In the current overfed dietary landscape of the industrialized world, this may result in obesity, non-alcoholic fatty liver disease, type 2 diabetes and other chronic metabolic diseases. Reducing food intake reduces mTOR activity and this reduction may be responsible in part for the increased lifespans observed in experimental animals subjected to fasting or caloric restriction. Owing to its multiple roles in cell signaling, inhibition of mTOR is highly promising as a therapy for numerous issues beyond diabetes and obesity, such as neurodegenerative disorders, cognitive decline, kidney disease and cancer.
Insulin and insulin-like growth factor-1 (IGF-1) are also major players in nutrient sensing. Chronic over-secretion of insulin is at the heart of metabolic syndrome and its associated comorbidities, which can certainly accelerate the aging process. Lower levels of these hormones are associated with better health and increased lifespan in model organisms. Insulin responds to numerous inputs but one of the most potent is refined carbohydrate. High-sugar diets are known to increase production of reactive oxygen species (ROS), so for healthy aging, a reasonable strategy might include caloric restriction across the board with an emphasis on restriction coming primarily via lower carbohydrate intake. (Indeed, the presence of the ketone bodies beta-hydroxybutyrate and/or acetoacetate has been shown to reduce production of mitochondrial ROS and increasing activity of antioxidant enzymes.)
While much is known about signaling pathways that influence aging in select organisms, human research is in its infancy. If there is indeed a genetic “switch” that flips somewhere around the sixth decade of life, there may not be much an individual can do to stop the aging process entirely or reverse it and actually get younger at the cellular level. But remaining metabolically healthy and maintaining cardiovascular and musculoskeletal fitness appear to be overarching ways people can stack the deck in their favor with an eye toward perhaps slowing the aging process and facilitating it happening more gracefully.