Apr 24, 2023 | Healthspan, OFAS News
Senior Scientist Sailendra Nichenametla, Ph.D., has been named as a recipient of the inaugural Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience Research, presented by the American Federation for Aging Research (AFAR) and Hevolution Foundation. Eighteen three-year awards of US $375,000 each have been granted to support research projects in basic biology of aging or geroscience—a research paradigm based on addressing the biology of aging and age-related disease to promote healthy aging. Dr. Nichenametla will utilize the funds to investigate the role of serinogenesis in regulating lipid metabolism.
The inaugural awards support talented early career investigators at research institutions around the world, including Albert Einstein College of Medicine, Boston University School of Medicine, Mayo Clinic, and the University of Wisconsin-Madison.
“In partnership with AFAR, Hevolution Foundation is excited to strengthen the international pipeline of aging researchers through the New Investigators Awards,” shares Felipe Sierra, PhD, Chief Scientific Officer, Hevolution Foundation. “We want to help fill the void and speed the pace of scientific discovery on the processes of aging by dramatically increasing the research workforce. This initial round of grants is a significant step toward that goal.”
Recipients of the New Investigator Awards were selected through a rigorous, peer-review process. Applications were reviewed by established aging researchers who volunteer their time and expertise to select scientists and research projects that have the greatest likelihood of making significant contributions to help us stay healthier longer as we grow older.
To learn more about Dr. Nichenametla’s research, visit www.orentreich.org/nichenametla-lab. For more information on the Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience visit www.afar.org/funding-opportunities.
Apr 17, 2023 | Healthspan
The hypothalamus is an area of the brain responsible for regulating a wide range of bodily functions, including metabolism, body temperature, and hormone production. This region also plays a key role in regulating the body’s circadian rhythms and the sleep-wake cycle, both of which undergo significant dysregulation as we age. These changes can have a cascading effect on other physiological systems, leading to a decline in overall health and an increased risk of age-related diseases such as diabetes, cardiovascular disease, and neurodegenerative disorders. For this reason, maintaining hypothalamic function has been considered important in maintaining good overall health while aging.
Inflammation is found to be increased in the tissues of aging organisms and is thought to exacerbate the aging phenotype—so much so that the term “inflamm-aging” has been derived from this phenomenon. It has been reported that the hormone menin is a crucial inhibitor of neuroinflammation in the hypothalamus. A recent study has investigated the importance of maintaining hypothalamic function and how diminished menin levels contribute to age-related dysfunction (Leng L, Yuan Z, Su X, et al. Hypothalamic Menin regulates systemic aging and cognitive decline. PLOS Biology, 2023: 21(3):e3002033 https://doi.org/10.1371/journal.pbio.3002033)
While it is primarily known for its role in regulating cell growth, menin also plays a critical role in the hypothalamus, where it modulates the hypothalamic secretion of various hormones involved in the regulation of organismal growth and metabolism. Menin interacts with a variety of proteins in the hypothalamus to regulate the expression and secretion of these hormones, and disruptions to menin’s function can lead to abnormal hormone levels and associated health problems. As a result, menin is an important hypothalamic hormone, taking a central role in regulating hormone secretion and maintaining overall health.
Age-related decline in menin has led researchers to consider its role in the context of aging. To elucidate the effects of decreased menin, researchers designed a genetically modified mouse that allowed them to express lower amounts of this hormone in the hypothalamus. This modification resulted in a mouse with characteristics of accelerated aging. Their findings revealed that decreasing menin in younger mice resulted in elevated hypothalamic neuroinflammation and several aging-related characteristics such as decreased bone mass and skin thickness, cognitive decline, and a slightly reduced lifespan.
Loss of menin also led to reduced levels of serine, an amino acid known for its neurotransmitter activity. The authors demonstrated that this reduction was caused by a decrease in the activity of an enzyme involved in its synthesis, which was regulated by menin. Surprisingly, reducing levels of menin in the hypothalamus also led to a reduction of serine levels in the hippocampus, suggesting some interplay between these two regions of the brain with regard to serine biosynthesis. A separate region of the brain, the hippocampus is the center for memory and learning.
To determine whether restoring menin levels could reverse age-related physiological changes, the researchers induced the expression of the menin gene in the hypothalamus of elderly mice (20 months old). Thirty days later, they observed an improvement in skin thickness and bone mass, as well as enhanced learning, cognition, and balance. These positive cognitive effects were associated with increased serine levels in the hippocampus. In addition to cognitive improvements, menin overexpression was sufficient to extend lifespan.
To investigate serine’s ability to rescue the age-associated detriments of an impaired hypothalamus, genetically modified mice lacking menin and, consequently, having low levels of hypothalamic and hippocampal serine, were supplemented with dietary serine. These mice were designed to emulate the neuroinflammation of aging and were previously shown to have impaired memory and cognition. Although serine supplementation showed improvement in the cognition and memory of these mice, it was not sufficient to extend the lifespan or produce benefits observed when menin had been overexpressed. This might be due to additional downstream actions of menin independent of serine biosynthesis.
Aging is known to be coincident with the degradation of multiple physiological systems. In the absence of the ability to treat a central underlying cause of aging, therapies that can discretely bolster individual systems would be effective in maintaining a quality of life with advanced age. With age, a decline in cognitive faculties is an unavoidable reality. This study provides evidence that dietary supplementation with serine, found at high levels in soybeans, eggs, fish, and nuts, might delay the onset of age-related cognitive impairment.
Mar 7, 2023 | Healthspan
Senescence and Aging
In 1961, Leonard Hayflick first observed that cultured cells ceased replicating after a finite number of divisions. Referred to as the Hayflick limit, a cell reaching this state enters into a permanent state of senescence. In addition to this hard limit, insults to the cell such as chemotherapy, hypoxia, and heat shock can also halt cellular replication and force cells into premature senescence.
While senescence plays an important role in promoting tissue repair, embryonic development, and regulating disease progression, it can also negatively impact aging.
Contemporary thought suggests that senescence provides a protective benefit in the short term but over time becomes detrimental. It is thought to be an example of antagonistic pleiotropy, a concept originally described by the evolutionary biologist George C. Williams. The concept is that natural selection can favor traits that confer a fitness advantage early in life but cause deleterious effects later in life. As an example, a cancerous cell might be forced into senescence to protect a younger organism by preventing the development of a disease state; however, the accumulation of senescent cells over the lifespan proves to be a detriment in later years.
Although senescent cells can no longer divide, they are not inert. These cells secrete chemical signals which contribute to an adverse environment, negatively affecting otherwise normal, healthy cells. This phenomenon has come to be known as the senescence-associated secretory phenotype (SASP) and is a prevalent factor of aging.
Studies have shown that the selective removal of senescent cells reduces the SASP and improves the health of an organism while extending its lifespan. Senolytic therapies have been designed to selectively remove these cells while leaving healthy cells intact. This is most often achieved by targeting specific features or pathways that are unique to these cells. Unfortunately, these therapies can be costly, moderately invasive, and often require a great deal of technical expertise.
Researchers from the University of Texas have provided preliminary evidence for a mechanical method to reduce the burden of senescent cells utilizing a low-cost, non-invasive application of low-frequency ultrasound therapy (Kumar S, et al. Rejuvenating Senescent Cells and Organisms with Only Ultrasound. bioRxiv 2022.12.08.519320).
Study Results
The authors hypothesized that brief, periodic treatment with low-frequency ultrasound (LFU) can rejuvenate senescent cells. To explore the efficacy of this therapeutic approach, the authors used cultured cells that were chemically induced into a senescent state. As is typical, these senescent cells lose their replicative capacity, exhibit an increased SASP, and undergo distinct changes to their cellular and mitochondrial structure. Cultures of these cells were treated with LFU for 20 minutes and subsequently monitored for 12-15 days.
LFU treatment ameliorated the SASP and restored replicative capacity, allowing cells to grow at a rate similar to that of non-senescent cells for the duration of the experiment. Examining individual LFU-treated cells revealed that the presence of p21, a cell cycle-regulating protein and indicator of cellular senescence, was almost entirely absent. Additionally, the normal cellular and mitochondrial structure was restored. These promising results led researchers to investigate LFU’s potential efficacy for treating the senescent cells of living animals, an important matter with regard to the potential for future clinical application.
Aged mice (22–25 months old) were treated with LFU, and a battery of tests was performed to assess both the effect on senescent cell burden and overall health.
Grip strength and treadmill running, two standard laboratory tests negatively correlated with age, were used to assess the general fitness of mice. LFU-treated mice performed significantly better in both tests when compared to control mice. The improvements seen in LSU-treated mice were similar to those seen in an additional group of mice that were subjected to exercise. Exercise itself is known to forestall age-related decline and improve cellular senescence.
To assess LFU’s effect on senescent cell populations in live animals, a second mouse experiment examined multiple molecular markers of senescence in the cells of both the kidneys and pancreas of LFU-treated animals. All molecular markers examined were significantly decreased as a result of LFU treatment, consistent with an improvement in senescent cell burden. One marker in particular, b-galactosidase, was decreased by as much as 70% when compared to untreated animals.
The ever-growing evidence implicating cellular senescence as a key driver of aging has demonstrated the importance of therapies targeting senescent cells. Previous experiments have shown the efficacy of senolytic therapies in eliminating these detrimental cells, improving both healthspan and lifespan. This study proposes a unique method to reduce the senescent cell burden through a transformative process and would likely achieve a benefit similar to senolytic therapies.
Feb 9, 2023 | Healthspan
The information theory of aging suggests that aging results from the accumulation of errors in an organism’s genetic code over its lifespan. The theory proposes that, as cells divide and replicate, their genetic information is subject to errors such as mutations or epigenetic changes. These errors can accumulate over time, leading to a decline in the functioning of cells, tissues, and organs, that ultimately results in aging. The theory also suggests that aging may be a form of “error catastrophe” in which the accumulation of errors in the genetic code reaches a critical point, leading to a decline in the overall functioning of the organism. However, it has been reported that genetic mutations are not as catastrophic as predicted. What might be of greater importance is the maintenance of molecular modifications residing on the surface of DNA. These epigenetic modifications act as an additional layer of genetic control and are vitally important for such things as cellular development, maintaining the specific character of specialized cell types.
Epigenetic modifications include DNA methylation, histone modification, and non-coding RNA molecules. These can be passed down from one cell generation to the next and play a crucial role in development, as well as in disease and aging.
Dr. David Sinclair et al. have published work describing both the importance of maintaining epigenetic fidelity and a means to reverse the loss of epigenetic information (Yang JH, et al. Loss of epigenetic information as a cause of mammalian aging. Cell. 2023;186(2):305-326.e27).
The Epigenome and How It Drives Aging
A common metaphor used to describe the relationship between the epigenome and DNA is that of a conductor and a musical score. Just as a conductor has the ability to interpret and control the performance of a musical piece, the epigenome controls the expression of the underlying DNA sequence. If the musical score is perfectly intact yet the conductor is impaired, then the execution of the piece deteriorates and potentially fails.
The epigenetic landscape is a dynamic and changing pattern of chemical modifications to DNA and its associated proteins that regulate gene expression. To understand the dynamics of the epigenome, consider the concept of the Waddington landscape, a visual representation of the process of cellular differentiation and development, named after the British developmental biologist Conrad Waddington.
The Waddington landscape is depicted as a multi-dimensional terrain, with different points representing different developmental outcomes. According to Waddington, cells move along valleys on the landscape as they differentiate into the necessary specialized cells, and the final developmental fate of a cell is determined by the particular valley it ends up in. The hills and valleys of the landscape represent the stability of different cell states. A hill represents the stability in maintaining correct developmental outcomes; a degraded hill allows for an environment in which a cell might easily switch between different cell states. The epigenome comprises this landscape of hypothetical hills and valleys, defining the nature of individual cells and holding them to that fate.
With increasing age, cells fail to maintain the fidelity of their epigenome, a phenomenon known as epigenetic drift. The causes of this perturbation to the epigenome are not fully understood. Ironically, one suspected cause is a mechanism for repairing damaged DNA, specifically the severing of both strands comprising DNA’s double helix structure. It is thought that subsequent to repair, the epigenetic modifiers at these double-strand breaks are lost or relocated. Over time these repairs can significantly alter the epigenetic landscape, resulting in a loss of cellular identity and systemic cellular dysfunction. In their recent paper, the Sinclair group demonstrated the validity of this through the development of a system in mice that induces double-strand breaks, the result of which is a phenotype of accelerated aging. Importantly, the double-strand breaks and the subsequent repairs do not result in mutations to the genetic sequence but do alter the epigenetic modifiers at these locations, demonstrating that the acceleration of aging in these animals is a result of epigenetic and not genetic alterations.
Yamanaka Factors—Reversing Aging Through Restoration of the Epigenome
The Yamanaka factors are a set of four transcription factors (Oct4, Sox2, Klf4, and c-Myc) that were discovered by the Nobel Prize-winning researcher Shinya Yamanaka. These factors have the ability to reprogram mature cells by resetting the epigenetic marks on DNA and its associated proteins, such as histones, to a more embryonic-like state. This resetting of the epigenome results in changes in gene expression, allowing cells to become pluripotent and capable of differentiating into any cell type. Although the mechanism through which these factors restore the epigenetic landscape is not fully understood, their utilization can reverse the effects of epigenetic dysregulation seen in aging. Numerous recent studies have leveraged the utility of these factors to delay aging or, in some cases, to rejuvenate specific tissues and organ systems.
In an attempt to repair the accelerated aging observed in mice as a result of the induced epigenomic changes, Sinclair et al. forced the expression of select Yamanaka factors, Oct4, Sox2, and Klf4. In doing so, the epigenetic marks of these mice were restored to a youthful state consistent with mice that had not been subjected to the epigenetic disruption caused by double-strand breaks.
This study provides strong evidence that the progression of aging is driven by the cell’s reaction to DNA damage and the subsequent loss of epigenetic information, not by the introduction of mutations. This is consistent with aging following a predictable sequence of molecular and physiological changes, even though DNA damage can occur randomly in the genome. Importantly, these results bring greater clarity and understanding to the molecular drivers of aging and will aid in the pursuit of therapies to combat aging and its associated diseases.
Jan 12, 2023 | Healthspan
A recent study published in The Journal of Clinical Endocrinology & Metabolism has shown a dietary approach that might reverse type 2 diabetes for millions of people currently suffering from this disease. Moreover, this approach costs nothing and does not require the use of pharmaceutical therapies.
Type 2 Diabetes
Type 2 diabetes is a chronic condition that occurs when the body becomes resistant to the effects of insulin, a hormone that regulates blood sugar levels, or when the pancreas is unable to produce enough insulin to maintain normal blood sugar levels. It is the most common form of diabetes, accounting for approximately 90-95% of all cases.
Type 2 diabetes can have serious health consequences if left untreated, provoking a range of complications including heart disease, stroke, kidney disease, blindness, nerve damage, and amputation. People with type 2 diabetes are also at an increased risk of developing high blood pressure and high cholesterol, which can further increase the risk of these complications. It is important for individuals with type 2 diabetes to carefully manage their blood sugar levels and make lifestyle changes, such as eating a healthy diet and getting regular exercise, to prevent or delay the onset of these complications.
Historically, the costs of diabetes have been a major burden for both individuals and society. In the United States, the total direct and indirect costs of diabetes were estimated to be $327 billion in 2017; this includes the cost of medical care, as well as lost productivity and reduced quality of life, and is expected to reach $532 billion by 2030. The projected cost of diabetes is of concern as the prevalence of the disease is expected to increase in the coming years. It is estimated that the number of people with diabetes will reach 439 million by 2030, and 592 million by 2035. This increase is largely due to the aging population and the increasing prevalence of obesity, which is a major risk factor for type 2 diabetes. The rising cost of diabetes will have significant implications for both individuals and society, and efforts to prevent and manage the disease are important in order to reduce these costs.
Intermittent Fasting
Intermittent fasting is an eating pattern that involves cycling between periods of eating and fasting. It is not a diet in the traditional sense, as it does not specify which foods to eat, but rather when to eat.
Intermittent fasting has a long history, with roots in various social, cultural, and religious practices. In many cultures, fasting has been a common practice for spiritual or religious reasons, with people abstaining from food and drink for certain periods of time as a way to purify the body and mind or to show devotion to a deity. This approach has also been used as a way to improve health and wellbeing, with some traditional medical systems, such as Ayurveda in India and traditional Chinese medicine, recommending fasting as a way to cleanse the body and promote healing.
Clinically speaking, intermittent fasting has been shown to have numerous health benefits, including weight loss, improved insulin sensitivity, reduced inflammation, and improved heart health. It may also have benefits for brain health and may even help to reduce the risk of certain diseases, such as cancer and Alzheimer’s disease. However, more research is needed to fully understand the long-term effects of intermittent fasting and to determine the extent of its benefits and the best approach for individuals.
Study Results
This recent study examined the effectiveness of Chinese Medical Nutrition Therapy (CMNT), an intermittent fasting diet, in achieving diabetes remission. Participants having a normal to overweight BMI between the ages of 38 and 72 who had been living with type 2 diabetes for 1 to 11 years and previously requiring the use of insulin or other antidiabetic therapies were randomly assigned to either the CMNT (intermittent fasting) or control group. The study intended to examine the effect of CMNT relative to diabetes remission as defined by the maintenance of a consistent HbA1c level—a well-established measure of glucose metabolism and indicator of type 2 diabetes—below 48 mmol/mol for at least three months after discontinuing all antidiabetic medications. In addition to HbA1c level, fasting blood glucose level, blood pressure, body weight, and quality of life were also observed.
Participants were assessed after 3 months of intervention and at 3 months post-intervention. In addition, the researchers conducted a 12-month follow-up to see if remission was sustained.
In the CMNT group, 47.2% of participants achieved diabetes remission after completing the 3-month intervention and 3-month follow-up. In contrast, only 2.8% of the control group achieved remission. The body weight of participants in the CMNT group was reduced by an average of 13.1 pounds, while the body weight of participants in the control group was reduced by an average of 0.6 pounds. During the 12-month follow-up period, 44.0% of participants in the CMNT group still maintained a state of diabetic remission.
Unsurprisingly, the study also found that participants with shorter diabetes duration, lower HbA1c levels, and fewer antidiabetic medications at baseline were more likely to achieve diabetes remission. In addition, the study found that the CMNT diet was associated with persistent improvements in HbA1c level, fasting blood glucose level, blood pressure, and quality of life.
This research indicates that an intermittent fasting dietary approach might offer a promising tool for the clinical management of type 2 diabetes. Further research is needed to understand its long-term sustainability and mechanisms of action.
Dec 7, 2022 | Healthspan
The Mediterranean diet—high in nuts, olive oil, and vegetables with a moderately reduced but varied consumption of fish, meat, and dairy—has gained notoriety as an ideal diet for human health. Populations in regions from which the diet draws its name are protected against a variety of diseases, including diabetes and cardiovascular and metabolic diseases. The imparted health benefits are believed to be attributable to a variety of compounds in the diet’s plant-based components known as polyphenols. Recent work published in BMC Medicine has found that polyphenols likely contribute to the health benefits provided by the Mediterranean diet, and further enrichment of these compounds in the traditional Mediterranean diets reduces unhealthy visceral fat.
Visceral fat, the bad one
Not all fat is created equal. Fat depots in the body are characterized by their location and function. Subcutaneous fat, lying just below the skin, is considered to be relatively inert; however, visceral fat, located deep within the abdominal cavity, has been associated with an increased risk of cancer, cardiovascular disease, and type 2 diabetes.
Even in individuals at a healthy weight, dyslipidemia—a condition marked by disproportionally large amounts of visceral fat—can result in increased systemic inflammation through the secretion of hormones known as adipokines. This “hidden” fat, popularly referred to as TOFI (thin outside, fat inside), has complicated the use of percent body fat and body mass index (BMI) as reliable metrics for health.
Polyphenols
Polyphenols are a loosely categorized and diverse group of chemicals containing a phenol ring and commonly found in plants. Their consumption has for many years been associated with positive health outcomes. It is thought that this group of chemicals provides both antioxidant and anti-inflammatory benefits, aiding in the prevention of cardiovascular disease, type 2 diabetes, and hypertension; however, the effects of polyphenol consumption on obesity are not well known.
The traditional Mediterranean diet, containing a relatively high amount of plant food sources, is rich in polyphenols and has been shown to enhance the reduction of visceral fat when paired with moderate exercise. Recent trials have set out to determine if a further increase of polyphenols alone is sufficient in reducing the amount of visceral fat.
DIRECT-PLUS Trial
The 18-month Dietary Intervention Randomized Control Polyphenols Unprocessed (DIRECT-PLUS) trial examined the effects of a modified Mediterranean diet containing fewer red and processed meats and more polyphenols (green-MED diet). In order to attain high levels of polyphenols, the green-MED diet was supplemented with green tea and mankai duckweed (Wolffia globose), two plants rich in polyphenols and thought to provide health-related benefits.
When compared to both a diet formulated along healthy dietary guidelines and a traditional Mediterranean diet, the green-Med diet showed an improvement in adiposity through the reduction of visceral fat depots. Although both styles of Mediterranean diet provided some form of weight loss, the green-Med diet showed a reduction in visceral fat twice that of the traditional Mediterranean diet. In accordance with the reduction of visceral fat, the green-Med diet improved the profile of circulating lipids, improving both triglyceride and cholesterol levels.
Another fat depot found deep within the abdominal cavity, deep subcutaneous adipose tissue, was found to be equally reduced. This fat is structurally similar to the subcutaneous fat found beneath the skin but, much like visceral fat, the accumulation of this fat is associated with impaired glucose metabolism. The reduction of deep subcutaneous fat in the subjects fed a green-MED diet was, as expected, associated with improved markers of glucose metabolism.
Findings such as these support ever-growing evidence that achieving a healthy diet and healthy amounts of body fat are more nuanced than simply accounting for calories or body fat percentage. Food sources, especially plants, contain chemicals that seem to act directly on metabolic pathways similarly to the actions of pharmaceuticals. Understanding and utilizing dietary components such as phytochemicals can contribute to a dietary regimen optimized for human health.
