According to the CDC, an estimated 5.8 million people over age 65 suffer from Alzheimer’s disease (AD), a population predicted to triple by 2060. This statistic foreshadows a bleak future for caregivers. Over the last century, medical and technological innovations have led to the average U.S. lifespan rising from 60 to 79 years; however, 1 in 10 Americans over 65 and half of those over the age of 85 are at risk of developing AD. The increased odds of developing AD with age have led to the tragic irony of a long life with a high chance of a diagnosis of this deleterious disease. Although a personal tragedy, there will be an equally catastrophic societal impact, and the increased burden might threaten to collapse our health care systems. The startling reality of this predicted scenario has led the U.S. to pass the National Alzheimer’s Project Act in the hopes of facilitating and directing research to treat Alzheimer’s disease and related dementias through increased funding. Despite this effort having increased yearly NIH funding seven-fold over the past decade, there has been very little progress in producing novel pharmaceutical interventions. In an effort to seek out improvements in this area of study, researchers from Cleveland Clinic have set out to repurpose drugs previously approved to treat other diseases with the hope of developing an effective treatment for AD.
In their Nature Aging publication, these researchers present a computational method with which they have identified a drug used to treat erectile dysfunction, sildenafil (trade name Viagra®), to be associated with a 69% decrease of AD incidence.
From a collection of over 1,600 FDA-approved drugs, computational modules identified 66 candidate compounds. These modules make use of algorithmic computer models that simulate real-world environments, in this instance modeling pathways biologically relevant to AD. Having these target drugs allowed for a retrospective analysis of over 7 million insurance provider patient reports, with which the incidence of AD could be referenced. This retrospective case-control study revealed several drugs to be associated with decreased incidence of developing AD; sildenafil was by far the most promising candidate.
AD is characterized by deterioration in brain function leading to severe cognitive impairment and dementia, ultimately resulting in systemic dysfunction and death. Histological analysis has found AD to be associated with the pathological accumulation of amyloid-β and tau proteins. Both proteins are thought to disrupt the function of brain tissue and contribute to AD by forming aggregate amyloid-β plaques and hyperphosphorylated tau tangles. Much of AD research has targeted these individual proteins; however, as the authors note, “the predisposition to AD is complex, polygenic and pleiotropic”, and previous efforts developed to discretely target these individual proteins have not yielded any effective therapies. Therefore, the authors set out to identify drugs that might act on the multiple underlying genetic and molecular pathways involved in the formation of both amyloid-β plaques and tau tangles and further interrogate these candidate drugs for their effectiveness in preventing AD.
Retrospective studies of this kind are powerful tools to observe associations, yet these types of studies are limited in regard to uncovering mechanisms that may be causal in driving the pathogenesis of disease. In order to gain mechanistic insight beyond sildenafil’s mere association with a lower risk of AD, researchers carried out experiments using cell types known to be affected by this disease. AD patient-derived induced pluripotent stem cells were differentiated into neuronal and microglial cells, and these cultured cells were subjected to treatment with sildenafil. Treated cells were observed to have reduced accumulation of pathogenic phosphorylated tau proteins, further suggesting that sildenafil might offer a benefit in the treatment of Alzheimer’s disease.
The authors of this paper intend to bolster these findings with subsequent mechanistic studies and a phase II randomized clinical trial with the hope of finding a therapy for a disease that has had very few innovations in treatment and is increasing in incidence at an alarming rate.
Nearly half of all adults in the U.S. are considered obese, and the incidence of obesity has steadily risen over time in nearly every first-world country. Adipose tissue (fat) has for many years been thought of as a relatively inert tissue functioning as a reserve depot during periods of low nutrient availability. However, research has revealed this tissue to be both metabolically and hormonally dynamic, playing a significant role in the overall health of an organism. More recently, research has uncovered evidence that adipose cells are highly susceptible to senescence, an irreversible state of non-proliferation, and the accumulation of senescent cells with age leads to the senescence-associated secretory phenotype (SASP)—a deleterious inflammatory condition thought to be a critical driver of age-related diseases. Obesity and age are top risk factors for developing type 2 diabetes, and it would seem that therapies aimed at reducing SASP would be an ideal approach to improve this condition.
P16, a protein critical in determining a cell’s fate and highly expressed in senescent cells, has been the focus of much of the contemporary research aimed at reducing SASP. The targeted elimination of cells highly expressing p16 has shown success in halting and even reversing age-related pathologies, although this approach has had only moderate success in treating the age-associated dysregulation of glucose metabolism, specifically insulin resistance, the impaired ability to respond to insulin. Recently, researchers have characterized a discrete population of senescent cells in adipose tissue expressing high levels of an alternate cell cycle protein known as p21. Furthermore, their findings suggest that specifically eliminating these cells may be more effective in preventing or reversing the development of age-related type 2 diabetes.
In their Cell Metabolism article, L. Wang et al. demonstrate that populations of senescent cells expressing high levels of p21 (p21hi) are distinct from those expressing high levels of p16 (p16hi), and that selectively eliminating populations of p21hi in mice improves glucose metabolism as well as or better than targeting p16-expressing cells alone. Importantly, the elimination of p21hi cells improves insulin sensitivity, whereas exclusive elimination of p16hi cells does not, a significant finding as insulin resistance is thought to be a key driver of type 2 diabetes in aging individuals.
Previous studies have used a variety of both genetic and pharmaceutical interventions to eliminate senescent cells with the hope of translating these findings from mice to people. (Pharmaceutical interventions are currently the preferred means of intervention as genetic therapies are still early in their development for clinical application.) Importantly, this particular study utilizes a combination of dasatinib and quercetin, an established pharmaceutical cocktail previously used to treat cancer, and may therefore be easily repurposed as a senolytic—a class of small molecules that target senescent cells with the aim of alleviating age-related diseases.
In recent years, treatment with dasatinib plus quercetin has been studied as a senolytic targeting cells expressing high levels of both p16 and p21. Although many senescent cells show elevated levels of both p16 and p21, Wang et. al demonstrate that there are distinct populations of senescent cells differentially expressing high levels of p16 and p21, and these populations may affect overall health in an independent manner. Further characterization of differing senescent cell populations and the specific role they play in disease may offer more effective and robust means of treating various age-related and metabolic diseases such as type 2 diabetes.
In 1935 Clive McCay published a paper demonstrating the pro-longevity effects of caloric restriction that would come to shape the future of longevity research. In McCay’s study, a simple 30% reduction of normal caloric intake was shown to impart robust gains in lifespan, becoming the accepted gold standard for lifespan-extending interventions. However, calorie restriction (CR) study designs continually incorporate one confounding factor. To achieve adequate beneficial caloric restriction, study animals are provided a daily, one-time meal, which they quickly consume in a matter of hours. This rapid consumption leads to a period of prolonged fasting between meals; therein lies the problem, as fasting has also been shown to provide benefits to both lifespan and healthspan. A study published in Nature Metabolism looks to address this long-standing issue and may lead to a complete rethinking of the calorie restriction model(CR).
In their recent publication, H. Pak et al. describe two novel feeding regimens designed with the intent of disentangling the once-per-day feeding behavior observed in typical CR studies. Diluted AL, a diet diluted with a non-digestible component providing 50% of the normal caloric density was made available to study animals continually; MF.cr, which provided the classic 30% caloric restriction, was provided in 3 meals per day. Through the use of these dietary regimens, researchers sought to gain insight into CR by eliminating both fasting and binging behaviors seen in previous experiments.
Similar to classic CR both of these non-fasting diets showed an improvement in body composition (reduced adiposity) and glucose metabolism (glucose tolerance). However, without a fasting component, these dietary interventions failed to achieve the increased insulin sensitivity and metabolic adaptions, such as increased fatty acid oxidation, typically seen in classic CR. Surprisingly, the chronic calorie restriction without fasting provided by the Diluted AL diet increased the frailty of experimental animals with age and was correlated to a decrease in quality of appearance, assessed by measuring standard factors such as coat appearance, kyphosis (skeletal posture), and distention of the abdomen. Moreover, without the benefit of a prolonged fast, calorie restriction alone was not only insufficient to extend but actually reduced lifespan when compared to animals given unlimited access to food, perhaps the most astounding finding of this study.
To further emphasize the role that fasting plays in classic CR, a third dietary regimen was created to discern if fasting alone was responsible for constituent metabolic adaptions. To provide an unrestricted amount of calories yet still maintain a prolonged fasting period, study animals were habituated to consume their full caloric intake within a 3-hour window and fast for the remaining 21 hours, what is referred to as a time-restricted diet (TR.al). This method resulted in a full recapitulation of the traditional CR diet with regard to body composition and metabolic adaptions (glucose metabolism, insulin sensitivity, and fatty acid oxidation) and further demonstrated that fasting is the critical component of classic CR.
This study makes clear that fasting is a potent means to achieve lifespan extension and, in the absence of fasting, chronic calorie restriction results in increased frailty and reduced lifespan, despite effectively reducing adiposity and circulating glucose. Taken together, these findings will compel further research to focus on the mechanisms involved in a fasting paradigm and reframe nearly a century of longevity research.
In the United States, more than 65% of individuals above the age of 50 have hypertension (abnormally high blood pressure). The occurrence of hypertension increases with age and is responsible for 7.6 million deaths per year globally (13.5% of total mortality). Additionally, 54% of strokes and 47% of cardiovascular disease (CVD, the leading cause of death worldwide) are attributable to high blood pressure. These factors make interventions targeting hypertension an effective means by which to improve the health and lifespan of an aging population. Pharmaceutical interventions are effective in treating hypertension but come with a multitude of side effects. As is often the case, exercise is a potent therapy for preventing age-related diseases such as hypertension; however, according to the CDC, only 5% of adults engage in the minimum recommended daily exercise required to reduce such diseases. New research might offer an alternative for those individuals who lack the time, motivation, or physical capacity to achieve the amount of daily exercise required to control hypertension and to stave off the deleterious effects of chronically elevated blood pressure.
A modified version of a technique known as inspiratory muscle strength training (IMST), a therapy originally developed to treat pulmonary disorders (e.g., COPD, sleep apnea), is showing significant potential in replicating various effects of daily exercise with to regard to cardiovascular health. Muscles involved in breathing can be strengthened by simply inhaling and exhaling for multiple uninterrupted repetitions through a handheld device similar in appearance to an asthma inhaler, which has the benefit of being low-tech, portable, and affordable.
The Journal of the American Heart Association recently published research by Craighead et al. wherein they utilize a high-resistance paradigm of IMST. Individuals aged 50-79 years having abnormally high blood pressure, but otherwise healthy, participated in a study examining the application of this modified form of IMST. Participants were required to perform 30 repetitions 5–7 times per week, which took a total of approximately 25–35 minutes each week. Study participants adhering to the regimen saw a change in their systolic blood pressure from around 135 mmHg to around 126 mmHg, a reduction that could, if persistent, correlate to a 30%–40% lower risk of death from CVD. These benefits are comparable to those seen in individuals who perform 150 minutes/week of moderate exercise. Notably, reduction in diastolic blood pressure was less than that seen for systolic blood pressure; however, the initial diastolic blood pressure for all subjects was normal, in contrast to elevated systolic blood pressure. Moreover, diastolic blood pressure is not known to increase with age.
In addition to blood pressure, the researchers observed improvements to a number of other facets known to be implicated in CVD, including endothelial function. The endothelium is a thin membrane of specialized cells lining the vascular walls, in part functioning to control the relaxation and contraction of blood vessels. Proper endothelial function is vital to healthy cardiovascular function and is also known to diminish with age. Craighead et al. report a 45% increase of flow-mediated dilation of the brachial artery (FMDBA), a clinical diagnostic that assesses the ability of a blood vessel to widen in response to an increase in blood flow volume. The increase of FMDBA in the treatment group correlated to a risk reduction of CVD incidence of 20–35%. A blood vessel’s ability to expand when subjected to increased blood flow is mediated by nitrous oxide (NO); not surprisingly, subjects undergoing IMST treatment were shown to have increased bioavailability of circulating NO.
This research explores IMST as a novel alternative to aerobic exercise that provides equivalent efficacy with regard to improving markers of cardiovascular function, yet requires a fraction of the time and physical exertion, resulting in greater adherence. All factors combine make this an ideal therapeutic for an aged population.
When contemplating organisms with extreme lifespans, a variety of examples come to mind: naked mole rats (30 years), bowhead whales (200 years), and even humans (80 years) are exceedingly long-lived relative to animals similar in both size and genealogy. Ants are not often associated with extreme lifespan; the typical lifespan of a worker ant is 1-2 years. A queen ant, however, can live up to 30 times longer, an astounding fact when you consider that worker and queen ants are genetically identical. Recently, researchers have uncovered another phenomenon in the ant world whereby genetically identical individuals exhibit vastly different rates of aging. In a paper published in Royal Society Open Science
, Beros et al.
detail an example of the extreme lifespan extension imparted to normally short-lived worker ants that have been infected by the tapeworm Anomotaenia brevis
In the natural world, parasitism occurs quite frequently with a variety of outcomes, often negatively affecting the quality of life. In contrast, parasitism by A. brevis in worker ants of Temnothorax nylanderi results in a lifespan at least 3 times longer than that of uninfected workers, and potentially extending to equal that of a queen. While most parasites do not cause acute or catastrophic detriment to their host, often there is an observable impairment to either lifespan or fitness. Beros et al. note that occasionally there are instances in such host-parasite systems whereby lifespan extension is imparted to the host; however, these benefits come at the cost of reduced reproductive health. Curiously, their recent studies not only characterize a parasitic relationship that provides the benefit of a robust lifespan, but one in which there seems to be no trade-off in reproductive fitness. These parasitized workers actually seem to have increased reproductive potential when compared to other fertile, yet not actively breeding, members of the colony known as nurses.
In an attempt to determine a mechanism for this phenomenon, researchers measured a variety of metabolic, physiological, and social characteristics exhibited by infected and uninfected ants. According to their observations, physiological changes to infected workers result in a phenotype more characteristic of colony members belonging to the nurse caste, including similar metabolic rates, body mass, and lipid content. Additionally, infected workers have a changed cuticular hydrocarbon profile (chemical secretions similar to pheromones) seemingly resulting in greater social caretaking being afforded to them, which again is similar to their nurse-caste colony-mates.
Although infected workers appear most similar to nurses, there may be other factors at play as nurses do not exhibit lifespans similar to queens. Previous studies by the authors have observed changes in gene expression brought about by this particular host-parasite system. These changes could represent potential novel targets of future studies and lead to insights into areas of the aging process that are as yet unexplored.
Unraveling the mechanism by which a parasite extremely alters ant lifespans could be informative to potentially extending the human lifespan.
OFAS Associate Scientist Dr. Sailendra Nichenametla will chair a webinar, “Sulfur Amino Acid Restriction – Moving from Animals to Humans”, for Aging Science Talks on October 20-21, 2021. The sessions will include presentations by Dr. Nichenametla, OFAS Associate Scientist Dr. Jay Johnson, and OFAS Assistant Scientist Dr. Zhen Dong. Dr. John P. Richie, Jr., (Penn State University College of Medicine), a member of OFAS’s Board of Scientific Advisors, will also be among the presenters. The complete program, including information on attending the Zoom sessions, is available here.
This series of talks was begun in March 2020 in response to the COVID-19 pandemic as a means of keeping aging researchers connected at a time when scientific conferences were being cancelled around the world. The talks have continued in webinar format with the support of the Glenn Foundation for Medical Research. For more information about the Aging Science Talks series, including dates and topics of upcoming talks, click here.