Category Archives: Anti-Aging Innovations

PHD3 Loss, Fat Metabolism, and Exercise Endurance

Tolerance of exercise and endurance can both decrease with age and declining metabolic health yet physical activity remains a cornerstone of physical and mental health regardless of age. Enzyme systems have received increasing attention for their potential to reduce exercise fatigue and improve endurance by providing the body with access to energy reserves and optimizing their use. Sugars are the primary fuel of cellular processes however, when nutrients are scarce – such as in cases of starvation or extreme exertion – cells switch to breaking down fats for energy. At this time, the mechanisms behind the rewiring of cellular metabolic pathways in response to fluctuations in resource availability are poorly understood.

New research published earlier this month in Cell Metabolism suggests a surprising consequence when one such mechanism is turned off – an increased capacity for endurance exercise. Recently conducted by researchers from the Harvard Medical School, the study revealed that blocking the activity of a fat-regulating enzyme in the muscles of mice could lead to an increased capacity for endurance exercise

Boosting Exercise Endurance in Mice

Led by Marcia Haigis, professor of cell biology at Harvard Medical School, a team of researchers investigated the function of the enzyme prolyl hydroxylase 3 (PHD3) – which they believed played a role in regulating fat metabolism in certain cancers. The study’s authors investigated the impact of PHD3 inhibition in genetically modified mice by carrying out a series of endurance exercise experiments.

Under normal conditions, PHD3 chemically modifies the enzyme ACC2 which prevents fatty acids from entering mitochondria to be broken down into energy. The team of researchers found that blocking PHD3 production in mice resulted in dramatic improvements in fitness measures: mice lacking the PHD3 enzyme ran 40% longer and 50% farther on treadmills and had a higher VO2 max – indicating increased aerobic endurance – than control subjects.

After endurance experiments, the muscles of PHD3-deficient mice revealed heightened rates of fat metabolism and an altered fatty acid composition and metabolic profile. According to the authors, their findings held true in genetically modified mice demonstrating that PHD3 loss in muscle tissues may be sufficient to boost exercise capacity.

PHD3 Enzyme Regulates Metabolic Pathways

After performing a series of molecular analyses to detail precise molecular interactions allowing PHD3 to modify ACC2 and how its activity repressed by AMPK, Haigis and her team reported that PHD3 and AMPK, another enzyme, simultaneously control the activity of ACC2 to regulate fat metabolism depending on energy resource availability.

Their research identified the critical role of the enzyme prolyl hydroxylase 3 (PHD3) in sensing nutrient availability and regulating the ability of muscle cells to metabolize fats, revealing that when nutrients are abundant, PHD3 acts as a brake inhibiting unnecessary fat metabolism that is released during exercise. Whole body or skeletal muscle PHD3 loss enhances acute exercise capacity during endurance exercise experiments.

“The findings shed light on a key mechanism for how cells metabolize fuels and offer clues toward a better understanding of muscle function and fitness,” the authors wrote.

“Understanding this pathway and how our cells metabolize energy and fuels potentially has broad applications in biology, ranging from cancer control to exercise physiology,” senior author Haigis explained. Although, further research is needed to identify whether this pathway can be manipulated in humans to improve muscle function, in the treatment of various diseases, and to better understand how PHD3 inhibition improves exercise capacity.

The latest findings carry implications for a potential novel approach to enhancing exercise performance, treating muscle disorders, as well as developing therapeutic methods for certain cancers in which mutated cells express decreased levels of PHD3. At this time, whether there are any negative effects – including weight loss, blood sugar changes and other metabolic markers – associated with PHD3 loss remains unknown although, this will hopefully be elucidated by future research.

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Reversing Age-Related Impairment and Immunity

While the average life-expectancy for humans continues to increase, a longer life span has been tied to an uptick in age-related disease and impairment across the globe. As a result of a declining immune system, the growing elderly population is more prone to infectious diseases – including influenza and COVID-19. Additionally, this group is commonly affected by age-related frailty, which has a significant negative impact on quality of life. The high level of care and involvement required to maintain the health of these patients has the potential to bear a growing burden on the healthcare system which is part of the reason underlying research efforts in the field of human longevity.

The current body of knowledge suggests the role of chronic low-grade inflammation in the biological aging process and development of age-related diseases; scientific evidence implicates that the presence of inflammation in the body accelerates aging. Hoping to uncover more information about additional factors that may contribute to an accelerated process and potential methods of reversing them, a team of researchers from the Department for BioMedical Research at the University of Bern conducted a study with findings published in Nature Metabolism.

Age-Related Frailty and Immunity

Under Bernese guidance, Dr. Mario Noti and Dr. Alexander Eggel aimed to identify new approaches to improving health-span in an ever-increasing aging population by focusing on adipose tissue eosinophils (ATEs) present in humans and mice. These immune cells found in visceral adipose tissue, otherwise known as belly fat, play an essential role in regulating inflammation and could be used to reverse aging processes; these cells are important in the control of obesity-related inflammation and metabolic disease as they are responsible for maintaining local immune homeostasis. Increasing age is tied to a decrease in eosinophils in adipose tissue and an increase in pro-inflammatory macrophages – turning belly fat into a source of pro-inflammatory activity.

Role of Eosinophils in Chronic Inflammation

The study’s authors demonstrated that visceral adipose tissue contributed to the development of chronic low-grade inflammation. They found that ATEs undergo major age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in human subjects as well as mice. However, exposure to a young systemic environment  was able to partially restore ATE distribution in aged subjects by reducing adipose tissue inflammation.

“In different experimental approaches, we were able to show that transfers of eosinophils from young mice into aged recipients resolved not only local but also systemic low-grade inflammation,” the researchers told ScienceDaily. ”In these experiments, we observed that transferred eosinophils were selectively homing into adipose tissue.”

Using an adoptive transfer or eosinophils from young mice to aged subjects, researchers were able to restore ATE distribution and sufficiently mitigate age-related local and systemic low-grade inflammation. As a result of the transfer, youthful systemic environments were restored and systemic rejuvenation took place in aged mice. Changes were both physical – assessed by endurance and grip strength tests – and immune-related – manifested in improved vaccination responses.

Dr. Noti and Dr. Eggel’s findings support the critical function of adipose tissue as a source contributing to accelerated aging and uncover the new role of eosinophils in sustaining adipose tissue homeostasis and thus, promoting healthy aging.

Because the age-related changes in adipose immune cell distribution were confirmed in human subjects, the latest study may have significant positive implications for the anti-aging medicine field when translated into clinical practice. Age-related frailty and immune decline may be halted and potentially even reversed as a result of this novel cell-based therapeutic approach.

“Our results indicate that the biological processes of aging and the associated functional impairments are more plastic than previously assumed,” Dr. Noti stated. “A future direction of our research will be to now leverage the gained knowledge for the establishment of targeted therapeutic approaches to promote and sustain healthy aging in humans,” his research partner Dr. Eggel concluded.


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Natural Compound Promotes Healthy Aging

The seven human sirtuins (SIRT 1-7), or NAD-dependent deacetylases, have been strongly correlated with human longevity due to their connection with metabolic function, aging, and the development of age-related diseases. In recent years, the protein SIRT1 has received the most attention due to its influence on gene regulation, genomic stability, and energy metabolism, garnering interest among the scientific community as a potentially viable pharmacologic therapy for the prevention of several health conditions, including type 2 diabetes, obesity, cancer, as well as cardiovascular and neurodegenerative diseases.

Several compounds have been found to impact the activation of sirtuins, including resveratrol which can be found in red wine, peanuts, pistachios, certain fruits, and cocoa. In small amounts, resveratrol may be able to replicate the health benefits of the steroid hormone estrogen, known for regulating reproduction, protecting against certain age-related diseases such as metabolic syndrome and Alzheimer’s disease.

A new study conducted in the United Kingdom aimed to uncover the mechanisms underlying resveratrol’s health benefits, its association with sirtuin proteins, and its ability to protect against age-related diseases; the latest findings were published in Scientific Reports.

Resveratrol and Healthy Aging

Small amounts of resveratrol – commonly found in red wine, berries, and chocolate – may be able to replicate the beneficial effects of estrogen in preventing metabolic diseases and cognitive decline. Larger amounts, on the other hand, may have the opposite effect, according to the study’s authors.

By activating estrogen receptors, the compound in turn activates sirtuin proteins to exert its physiological effects. Sirtuin proteins play a significant role in the healthy aging process as they control mitochondrial biogenesis, promote DNA repair, and help regulate metabolic function. They are believed to protect the body against several age-related diseases and are thought to have excellent potential drug targets according to the scientific community; however, clinical applications of the proteins remain unclear. Even still, there remains a lack of understanding of how sirtuin signaling translates to increased healthspan in human beings.

Studying Sirtuin-Activating Compounds

Led by Dr. Henry Bayele, molecular biologist at the University College London, researchers conducted an in vitro study of human liver cells which exposed them to a variety of dietary compounds aimed at activating sirtuin proteins. Collectively known as dietary sirtuin-activating compounds (dSTACs),  resveratrol and isoflavones, such as daidzein, are natural activators in comparison with other synthetic compounds developed to spur sirtuin signaling. Researchers found that at low doses, resveratrol increased sirtuin signaling in cells by mimicking estrogen although, at high doses it actively reduced signaling.

“Numerous studies in animals have suggested that these proteins could prolong healthy lifespan by preventing or slowing disease onset,” Dr. Bayele told Medical News Today. “But developing effective drugs or dietary interventions has been frustrated by a lack of a common understanding of how exactly they work in the body’s cells.”

The study’s findings support the notion that small amounts of red wine can promote healthy aging as can other dietary components; Dr. Bayele reported that the compound present in licorice, isoliquiritigenin, is even more effective at activating sirtuins. His research supports the claim that dSTACs can be viewed as “plant estrogens”, benefiting human health by performing functions that estrogen would typically be responsible for.

Implications for Anti-Aging

Emerging evidence supportive of resveratrol’s benefits could lead to the development of alternatives to hormone replacement therapy – which can increase the risk of cardiometabolic disease – for menopause patients. However, further clinical studies are required to confirm whether individuals using dSTACs as estrogen substitutes to promote healthy aging display positive results.

“Regular low doses of resveratrol, such as through moderate consumption of red wine as part of a healthy diet, may be able to provide the benefits of estrogen,” Dr. Bayele explained. “This would apply to both men and women of all ages, but postmenopausal women may feel these benefits the most because they have lower estrogen reserves than men of a similar age.”

Dr. Bayele and his colleagues caution that the effects of dSTACs on cells in vitro found in their study may not reflect their effects in human subjects. For instance, the body may digest resveratrol compounds in the gut or metabolize them in the intestinal microbiota. If they do survive digestion intact, the absorption of the compounds into the bloodstream may be poor or the liver may break them down during digestion. Hence why additional study is needed to develop novel strategies for effectively delivering resveratrol for maximum benefit.

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