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.
The mitochondrion, often referred to as the powerhouse of the cell, provides a valuable resource through the production of ATP, the cell’s energy, allowing cells to carry out a multitude of critical biological processes. Diminished mitochondrial function leads to inefficient production of ATP and metabolic dysfunction instigating the deterioration of the cellular environment, contributing to systemic failures and organismal degradation. With age, mitochondria become increasingly dysfunctional and are considered to be at least partly responsible for driving age-related pathologies. Research conducted at the Hebrew University of Jerusalem explores a novel class of compounds designed to help sustain mitochondrial function in an effort to improve both lifespan and healthspan.
In order to maintain a highly functional cellular environment, cells undergo autophagy, which removes and recycles aberrant molecules. Autophagy can be either selective, targeting specific organelles, or “bulk”, a non-selective degradation of molecules. A form of selective autophagy, mitophagy specifically targets dysfunctional mitochondria for removal while simultaneously replacing them with newly formed mitochondria—a process known as mitochondrial biogenesis—thus maintaining a healthy mitochondrial population. Both mitophagy and mitochondrial biogenesis have been shown to decline in aging animals, and the prevention of dysfunctional mitochondria has been shown to sustain a healthier organism throughout life.
Prior research has provided evidence that the polyamine spermidine could be key to mediating the activation of mitophagy. Spermidine, a small molecule found in living tissues and, interestingly, found at relatively high levels in many foods comprising the metabolically beneficial Mediterranean diet, is implicated in a variety of biological processes. When supplemented at the appropriate concentration, spermidine has been found to extend the lifespan of multiple organisms through the activation of mitophagy. However, excess spermidine results in the accumulation of toxic metabolic by-products such as acrolein, making it problematic as a pharmaceutical therapy. Current research has sought to provide the health benefits of spermidine without the production of toxic metabolites by engineering a class of structurally similar polyamines, referred to as mitophagy activating compounds (MACs).
C. elegans treated with spermidine are known to have increased mitophagy and an extended lifespan. The synthetically engineered molecule VL-004, a polyamine structurally similar to spermidine, has shown promise as a robust MAC. C. elegans given VL-004 show an extension of lifespan similar to that resulting from spermidine supplementation. As a result of the preservation of both muscle mass and motility and an improved stress response, VL-004-treated animals demonstrate an improvement in general health, in addition to increased lifespan. These benefits were shown to be entirely dependent on mitophagy, as subsequent experiments involving the deletion of critical mitophagy genes completely abrogated the effects of VL-004 treatment. VL-004 was demonstrated to be even more potent than spermidine regarding the activation of mitophagy and, importantly, has shown no evidence of generating toxic by-products such as acrolein. Subsequently, VL-850 was engineered based on VL-004’s structural properties; it has shown to be an even greater MAC, increasing mitophagy in both C. elegans and cultured human cells.
Research is increasingly producing novel pharmaceutical interventions to improve the quality and duration of human lifespan. The hope is to one day incorporate such compounds into a clinical standard of care targeting mitochondria to help stave off the ill effects of aging but also to aid in non-geriatric diseases wherein mitochondrial dysfunction results in deleterious health outcomes.
Cannabidiol (CBD), a non-hallucinogenic compound derived from the Cannabis sativa plant, has become a popular and effective supplement for treating ailments from chronic pain to epileptic seizures, and evidence has emerged that CBD extends the lifespan of specific animal models. Although CBD has shown efficacy in treating a variety of maladies, there is a lack of mechanistic data supporting how these effects are achieved. A recent study published in Geroscience has linked CBD’s lifespan-extending properties to a well-characterized cellular process known as autophagy.
Derived from the Greek word “autóphagos” meaning self-devouring, autophagy is the body’s process of recycling cells or cellular components. This maintenance is critical to cellular health. Many of the interventions known to extend lifespan involve autophagy: methionine restriction depends on it; exercise and intermittent fasting stimulate it. Diminished autophagic processes persistently characterizes aging in all manner of species. Furthermore, genetic modifications designed to upregulate autophagy have been shown to extend lifespan in a variety of lifeforms from yeast to mice.
C. elegans, the animal model for this particular study, is a roundworm frequently chosen for aging experiments due to its short lifespan and readily tractable genetic character, allowing for a variety of experiments designed to parse out the biological underpinnings of an experimental intervention. Previous studies had demonstrated a significant extension of lifespan in C. elegans supplemented with CBD; in this most recent study, the imparted increase in lifespan is shown to be dependent on autophagy and to protect against age-related neuronal degeneration.
Animals treated with CBD were roughly 25% longer lived. To demonstrate that the observed increase in lifespan was dependent on autophagy, investigators genetically inhibited the action of several autophagy genes (bec-1, vps-34, and sqst-1); in doing so, they deterred the CBD-attributed increase in lifespan. Further tissue-specific interrogations revealed autophagy to be markedly increased in neurons and resulted in a morphology more similar to younger neurons. The authors interpret CBD’s activation of autophagy and subsequent improvement to neural systems to be responsible for the increased lifespan seen in these animals.
Lifespan, although an important metric for anti-aging therapies, is strictly a chronological assessment. Healthspan is a functional measure relative to chronological age. Numerous biological parameters decline with age; however, an intervention that is considered to improve healthspan will retain or restore a particular function to a state seen earlier in the lifespan of an organism. In addition to increased lifespan, CBD treatment improved healthspan in several areas, e.g., motility, reproduction, and neuromuscular function. Overall, these data demonstrate that CBD allows animals a functionally higher quality of life for a longer period of time.
Neuronal degradation is characterized as deterioration in both cognitive and neuro-muscular function and is a common hallmark of aging. Delaying this phenomenon could directly increase lifespan; however, the possibility of improved healthspan is equally significant. In human populations, the likelihood of developing a neurodegenerative disease goes up exponentially in aged populations. As an example, consider that the risk of developing Alzheimer’s disease (the sixth leading cause of death in the United States) doubles every five years after the age of 65; with an average life expectancy of roughly 79 years, this is a bleak statistic. As more research focuses on cannabidiol, there presents an opportunity to uncover previously unknown benefits of cannabis-derived compounds to address such issues. Although this study does not suggest a direct link to any particular neurological disease, such as Alzheimer’s disease, the inordinate neurological pathologies as well as non-pathological age-related cognitive decline seen in the elderly suggest a potentially beneficial pharmacological use.
OFAS presented the third Dr. Norman Orentreich Award for Young Investigator on Aging to Maximilian Schmid-Siegel, a Ph.D. candidate at the Medical University of Vienna Institute of Medical Genetics (Vienna, Austria). The award was presented at the 15th International Symposium on Neurobiology and Neuroendocrinology of Aging, Bregenz, Austria. Maximillian was selected for his presentation “Ribosome heterogeneity by rRNA methylation in skin cell senescence”.
This award is intended to inspire young investigators to continue aging research and to acknowledge the potential of their work. In addition to the US$1,000 prize, Max was invited to present at the 2023 OFAS Symposium on Healthy Aging.
Symposium organizer Holly Brown-Borg, recipient Maximillian Schmid-Siegel, OFAS Deputy Director of Research Jay Zimmerman.
An intermittent variation of the dietary intervention methionine restriction protects against obesity and provides additional metabolic health benefits to mice, according to a study from the Johnson Laboratory, recently published in Aging Cell.
The results of this work are important in that they suggest that a limited period of dietary intervention (i.e., only three days per week) may be sufficient to produce the anti-aging effects associated with continuous methionine restriction. Such an approach could allow people to eat as normal for the majority of the week, but still receive the health benefits described for continuous methionine restriction.
Methionine restriction has been shown to protect rodents against diet-induced obesity and can extend their healthy lifespan by up to 45%. Promisingly, recent studies have suggested that the effects of methionine restriction on health and lifespan are likely to be conserved in humans. Given that the vegan diet is low in total protein and amino acids, methionine restriction is possible for people. However, such a diet might not be practicable or desirable for everyone.
As a result, the Johnson Laboratory sought to develop a version of methionine restriction that produces the same benefits as the continuous intervention, while also being more convenient and easier to perform. They were inspired by published reports that intermittent forms of other health-promoting interventions (i.e., the ketogenic diet and calorie restriction) are similarly effective to their continuous counterparts.
The team first tested whether two increasingly stringent versions of intermittent methionine restriction offered the same protection against obesity as the continuous intervention. They fed male mice one of four high-fat diets: 1) a control diet containing typical amounts of methionine, 2) a continuously methionine-restricted diet, 3) a diet containing typical amounts of methionine for four days, followed by a methionine-restricted diet for three days, and 4) a diet containing typical amounts of methionine for four days, followed by a diet completely lacking methionine for three days. The authors found that the more stringent of the two forms of intermittent methionine restriction was just as effective as the continuous intervention in protecting against the dramatic weight gain and fat accumulation seen in mice fed the high-fat control diet. Similarly, the authors observed that intermittent methionine restriction also completely protected female mice against diet-induced obesity.
Next, they explored the effects of intermittent methionine restriction on physiological changes that normally result from continuous methionine restriction. For this purpose, they measured the levels of four metabolic markers (the hormones IGF-1, adiponectin, leptin, and FGF-21) in blood samples from previously treated mice. As expected, they found that intermittent methionine restriction resulted in changes similar to those of continuous methionine restriction. This finding is particularly interesting given that a body of evidence suggests that low IGF-1 levels are associated with an extension of healthy lifespan. So, it is likely that intermittent methionine restriction will produce an extension of lifespan similar to what has previously been observed for continuous methionine restriction.
Continuous methionine restriction (MR) extends the healthy lifespan of a number of model organisms, including rodents. A novel intervention featuring only three days of stringent MR per week (aka, intermittent MR; IMR) protects mice against diet-induced obesity, fatty liver (aka, hepatosteatosis), and dysregulation of blood sugar (aka, dysglycemia). It also produces beneficial changes in the levels of multiple energy-sensing and longevity-regulating hormones. As a result, IMR is likely a preferable health-promoting strategy to continuous MR.
“This is a very exciting result and actually one of the more significant findings to come from the Orentreich Foundation in recent years” notes senior author Dr. Jay Johnson, an Associate Research Scientist at OFAS. “In addition to protecting mice against diet-induced weight gain, intermittent MR also guards against the development of both fatty liver and dysglycemia. In fact, intermittent MR is actually more effective at maintaining normal blood sugar than classical MR … and this despite four fewer days of dietary intervention per week. Interestingly, mice undergoing intermittent MR also retain more of their lean body mass as compared with their continuously methionine-restricted counterparts. As a result, we consider intermittent MR to be a superior alternative to the classical intervention, and we hope that many of the benefits that it confers to mice will also hold true for humans.”
To view the article, published in Aging Cell, visit https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13629.
Modern science has scoured the planet for naturally-occurring compounds that might hold medicinal benefits. For example, rapamycin, perhaps the most well-researched compound known to extend the lifespans of multiple species, was isolated from a bacterium found in the soil of Easter Island. The natural world seems to hold a veritable pharmacy of compounds waiting to be discovered, and pharmaceutical companies continue to catalog samples from all corners of the globe, compiling an ever-growing library of compounds with which they interrogate all manner of biological pathways in the hopes of discovering the next ground-breaking drug. Of course, many cultures have spent centuries compiling their own medicinal libraries, mostly comprised of plants thought to be imbued with beneficial properties. The traditional Chinese medical pharmacopeia contains a multitude of specimens purported to improve healthspan.
A recent publication in Nature Communications examined numerous examples of plants commonly used in traditional Chinese medicine. Utilizing the lifespan assay known as the yeast mother enrichment program, researchers assessed crude extracts of candidate plants and identified the herb Psoralea corylifolia to have potential lifespan-extending properties. Further analysis demonstrated a single compound, corylin, to be responsible for improving lifespan; it was shown to function through the mTOR pathway, a well-defined pathway known to modulate lifespan in a multitude of organisms.
Although the mTOR pathway is highly conserved and its inhibition is known to extend lifespan in a variety of species including both yeast and mammalian, these species have significant differences. To explore if corylin’s actions in yeast might have a related effect in mammalian systems, the authors turned to in vitro experiments. Human umbilical vein endothelial cells treated with corylin showed significantly decreased markers of senescence, an important finding as senescence is highly correlated with aging in multicellular organisms and thought to be a driver of an aging phenotype. Additionally, gene expression patterns of older cells treated with corylin were similar to those of younger cells. These findings encouraged the authors to the expand the scope of their study to examine corylin effects in mice.
Mice were fed a high-fat diet similar to that of modern western peoples and known to induce multiple pathologies, e.g., obesity, cardiovascular disease, diabetes, dyslipidemia, and chronic inflammation. Interestingly, corylin supplementation did not reduce body weight, yet it improved numerous obesity-related pathologies. Circulating levels of total cholesterol (as well as HDL and LDL) and triglycerides were found to be reduced, suggesting improvement to cardiovascular health. Levels of aspartate transaminase and creatinine, common markers of liver and kidney function, respectively, improved in corylin supplemented animals. Additionally, fasting glucose was significantly reduced, suggesting systemic improvements in metabolic function despite corylin’s inability to reduce body weight due to a high-fat diet. In accordance with the metabolic improvement, corylin supplementation also improved the physical function of older mice, assessed via multiple standardized measurements to determine muscle strength, balance, and endurance.
Not surprisingly, the lifespan of corylin-treated mice was also shown to increase. Assessed at 102 weeks of age, 63.3% of animals fed a high-fat diet had died as compared to only 43.3% of the corylin-treated group. Additionally, survivability at earlier time points showed an even greater benefit to corylin-supplemented mice with a maximum improvement of 30%. The paper did not report the survival of all animals over the duration of their lives; however, having observed such significant differences in percent survival, it is reasonable to conclude that corylin will have a similarly sustained effect over the entire life of these animals.
Western diets are considered to be a major contributor to poor health and the acceleration of age-related disease. This is especially important in the context of this study considering the Western diet is analogous to the high-fat diet fed to the study animals and the various improvements to health parameters observed in corylin-treated animals. The Western diet is quickly becoming no longer relegated to Western peoples; many cultures around the world are adopting similar diets and as a result becoming subject to poor health outcomes. Corylin might have the potential to alleviate a portion of diet-induced stress seen in people consuming these less-than-ideal diets.