Why We Age: An Evolutionary Exploration
Biosphere 2, an ecological research facility nestled in Tucson, Arizona, holds a captivating tale of exploration and discovery. Constructed in the 1980s, its primary mission was to unveil the minimal environmental requirements for human survival, both on distant planets and on Earth in a post-apocalyptic world. Within its impressive glass walls were meticulously engineered microcosms, five distinct ecosystems — lush rainforests, sprawling savannas, arid deserts, serene marshes, and simulated seas.
In September 1991, eight intrepid souls, four men, and four women, embarked on an extraordinary mission within Biosphere 2. They would become the “guinea pigs” of a grand experiment, aimed at testing human resilience in an artificial ecosystem. With the facility sealed off from the outside world, they were left to fend for themselves for a remarkable two-year period.
Despite their physical isolation, Biosphere 2 remained a thermodynamically open system, receiving energy from the sun, allowing all the photosynthetic organisms within its confines to thrive. No materials entered or left the research facility. A staggering 85% of their food had to be cultivated by the participants-turned-farmers.
Among these subjects was a gerontology professor from UCLA, Roy Walford, who was renowned for his advocacy of a low-calorie diet as a path to longevity. Before entering Biosphere 2, they had calculated that they could coexist with the facility’s ecosystems, producing roughly 2,500 Kcal per person per day — sufficient to meet their daily caloric requirements. However, unforeseen technical issues caused them to produce only 1,700–2,000 Kcal per person per day.
These individuals unwittingly became subjects in an unprecedented experiment, a two-year-long foray into extreme calorie restriction. Although their food was nutritionally dense, its caloric content was lower than required by their bodies, leading to significant weight loss for all participants.
But the story doesn’t end with weight loss; the subjects underwent intriguing physiological changes. Their blood glucose levels dropped to an average of 76 mg/dL, blood pressure fell to an average of 90/45 mmHg, total cholesterol dropped to 125 mg/dL, and uric acid levels plummeted to 3.4 mg/dL.
While these laboratory and physiological changes might appear unusual, the participants remained healthy and fully functional. These shifts aligned with those observed in animal studies subjected to calorie restriction.
Did the participants’ human lifespan extend, similar to the effects observed in calorie-restricted animal experiments?
The results of their extraordinary experiment revealed the safety of extreme calorie restriction for humans, even under challenging environmental conditions. Long-term studies on calorie restriction in humans are challenging and ethically complex, prompting scientists to turn to primate subjects. Primates, with their genetic proximity to humans, are ideal candidates for extrapolating results to our own species, Homo sapiens.
So, the story of those experiment begins in the late 1980s when a group of scientists, led by Dr. Richard Weindruch, initiated a long-term experiment at the Wisconsin National Primate Research Center. They were inspired by earlier research on calorie restriction in rodents, which had shown that reducing calorie intake without malnutrition could extend lifespan and delay the onset of age-related diseases.
For this study, a cohort of rhesus monkeys was divided into two groups: one group was provided with a regular diet, while the other group was subjected to calorie restriction, receiving 30% fewer calories while maintaining essential nutrients. Both groups were carefully monitored throughout their lives.
As the years passed, it became evident that the calorie-restricted group of monkeys was experiencing remarkable health benefits. They displayed lower rates of obesity, diabetes, cardiovascular diseases, and cancer compared to the monkeys on a regular diet. The calorie-restricted monkeys not only lived longer, but they also aged more gracefully, maintaining better muscle mass and cognitive function in their old age.
Out of the original 76 monkeys, a striking difference emerged. A mere 13% (5 out of 38) in the calorie-restricted group succumbed to age-related issues, in sharp contrast to the 37% (14 out of 38) in the control group. In essence, this means that the calorie-restricted group exhibited a remarkable boost in longevity. It revealed a hazard ratio (HR) of 3.0, indicating that control animals had three times the risk of perishing from age-related causes compared to their calorie-restricted counterparts at any given point in time. The monkeys in the calorie-restricted group experienced cancer and heart diseases 50% less frequently than those in the control group. Furthermore, not a single monkey in the calorie-restricted group suffered from diabetes in their later years.
The findings of this study provided valuable insights into the potential benefits of calorie restriction on extending lifespan and delaying age-related illnesses in primates, which are more closely related to humans than rodents. The research team’s work fueled interest in the practice of calorie restriction in humans as a means of promoting longevity and healthy aging.
The story of the calorie restriction study on rhesus monkeys from the University of Wisconsin-Madison is a testament to the power of scientific curiosity and determination in unlocking the secrets of aging and promoting healthier, longer lives for both humans and our primate relatives.
However, why does calorie restriction effectively prolong lifespan? What unfolds within the bodies of living organisms when they limit their food intake?
To tackle these questions, we must first comprehend how living beings adapt to environments characterized by fluctuating food availability. When food is abundant, these creatures seize the opportunity to reproduce and generate numerous offspring. They don’t need to activate the many genes essential for repairing the wear and tear that naturally occurs within their bodies over time. Their primary aim is to pass on their genetic legacy, age gracefully, and eventually succumb, with their offspring perpetuating the cycle. In contrast, when food is scarce in their surroundings, their primary focus shifts from reproduction to sheer survival. Their goal becomes surviving the day to ensure they can reproduce when food once again becomes plentiful. At this point, every cell within their bodies ups the expression of antioxidant genes, capable of effectively neutralizing free radicals, DNA repair genes that can shield against or rectify DNA damage resulting from exposure to free radicals produced during metabolic processes, UV radiation from the sun, or toxic environmental chemicals. Additionally, genes involved in autophagy, a cellular process that essentially “self-cannibalizes” to break down and replace worn or dysfunctional structures, become more active.
From an evolutionary perspective, this metabolic shift, from a focus on reproduction to one of survival, stands as a pivotal adaptation. Those that produce many offspring when food is drastically scarce inadvertently jeopardize the survival of the entire group. This is because each individual must make do with minuscule food rations, often falling below the minimal sustenance level. Conversely, those who can restrain themselves from reproduction during such periods increase their chances of survival. This, in turn, allows them to produce more offspring in the future, once the environment becomes more conducive. It’s essential to note that this restraint isn’t a conscious choice but is influenced by genetic factors that are beyond the individual’s conscious control.
Calorie restriction activates the survival mode within an organism’s body and concurrently inhibits the reproductive mode. While this may result in decreased fertility, it dramatically enhances their ability to survive. What’s intriguing is the trade-off between infertility and survival. Such trade-off mechanisms appear to be fundamental across various biological systems, spanning a multitude of species. The results of studies involving animals, ranging from worms and flies to mice and even monkeys, consistently indicate that calorie restriction can extend their lifespans. In scientific terms, these natural phenomena are frequently explained by the Resources Reallocation Hypothesis (RRH).
The fact that fewer calories can lead to a longer life in mice points to the involvement of energy metabolism regulators in the calorie restriction process. This suggests that that calorie restriction-induced metabolic reprogramming may be a key event in the mechanism of life span extension.
So, which cellular programs are influenced by calorie restriction?
Cynthia Kenyon began her scientific journey as a molecular biologist and geneticist before venturing into the intriguing realm of biogerontology, a field dedicated to unraveling the mysteries of biological aging. Initially met with skepticism from many of her peers, who questioned the purpose and potential of her work in this field, Kenyon’s resolve remained unshaken. Her determination was best described in her father’s words, “There is a right way to do things and a wrong way. And then there’s Cynthia’s way.”
Kenyon proposed that if genetic factors played a significant role in the development of various diseases in the world, they should also play a crucial role in the aging process. She hypothesized the existence of a genetic switch that governed the duration of a living organism’s life.
In the early 1990s, Kenyon and her team at the University of California, San Francisco, embarked on an intriguing experiment. They sought to uncover the impact of mutating one specific gene, daf-2, on the lifespan of microscopic worms, Caenorhabditis elegans. The results were astonishing. Worms altered through Kenyon’s research could live twice as long as their unaltered counterparts. Typically, C. elegans worms have an average maximum lifespan of 21 days, entering old age around day 17 after hatching. However, Kenyon’s mutant C. elegans defied this norm. At day 17, they exhibited the behavior of much younger worms, even as they reached day 30. Imagine this phenomenon occurring in humans — individuals in their 70s retaining the vitality and actions of those in their 30s, still riding the waves at the beach or racing motorcycles, and living with vigor at the age of 150!
Subsequently, it was revealed that the daf-2 gene belonged to a class of highly conserved genes that transcended species. Its function was so fundamental in the biological systems of living organisms that analogous genes could be found in various, more complex creatures beyond microscopic worms. In mammals, a gene closely mirroring the function of daf-2 is the insulin receptor gene. This receptor is expressed on cell membranes and serves as the binding site for insulin, a hormone produced by pancreatic beta cells in response to elevated blood sugar levels following a meal. In terms of evolution, this receptor serves a critical role, not only as an insulin binding site but as an environmental food availability sensor. In times of abundant food, living organisms can consume substantial amounts, and the insulin receptor detects this through increased blood insulin levels as a response tho increased blood glucose.
The binding of insulin, in large quantities, to the insulin receptor activates cellular metabolic pathways associated with fertility while inhibiting genetic circuits related to self-maintenance. This aligns with the concept of Resources Reallocation Hypothesis previously mentioned. In an environment abundant with food, a living organism’s biological system allocates its resources to the generation of new individuals, while overlooking self-preservation and self-repair. Conversely, when food supplies diminish, it’s as though every cell in the body collectively cries out, “Alright, folks, listen up! We need to conserve our resources and channel all our efforts into survival through these challenging times. Let’s slow down the aging process!”
Kenyon’s groundbreaking discoveries were published in the esteemed scientific journal Nature in 1993. Kenyon’s groundbreaking work has demonstrated that the dream of extending the human lifespan is not a far-fetched Hollywood fantasy but a scientifically attainable reality. By uncovering the genetic pathways and molecular mechanisms that influence aging, her research has opened the door to potential interventions that could slow down the aging process and enhance human health and longevity.
As we look to the future, Cynthia Kenyon’s work serves as an inspiring reminder that our understanding of the biology of aging is continuously evolving, offering hope for a longer and healthier life for generations to come.
