Pill That Slows Aging? Meds May Boost Health Span

 All this earlier research which your INCOMPETENT? DOCTOR DID NOTHING! And you and the hospital president haven't fired them yet? Why are you tolerating incompetence when it impacts your recovery?

• Metformin (21 posts to July 2012)
• rapamycin (8 posts to May 2017)
• caloric restriction (16 posts to February 2012)
• senescent cells (12 posts to January 2016)
• biological aging (8 posts to August 2023)

The latest here:

Pill That Slows Aging? Meds May Boost Health Span

Aging is the strongest risk factor for most chronic diseases; however, medicine has historically treated each condition individually. Geroscience is a new discipline that aims to define and modify aging-related biological pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival.

A review in JAMA outlines the aims, methods, recent advances, and ongoing challenges of geroscience.

The review was authored by Stephen B. Kritchevsky, PhD, Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina, and Steven R. Cummings, MD, California Pacific Medical Center Research Institute, San Francisco, and Department of Epidemiology and Biostatistics, University of California, San Francisco.

In Italy, the prevention of aging is particularly relevant. Data from the Italian National Institute of Statistics (2023) show that 24.1% of the Italian population — 14.2 million people — is older than 65 years, making Italy the world’s second-oldest country after Japan.

By 2050, 35% of Italians are expected to be 65 years or older. 

The 2023 Osservasalute Report found that 87% of Italian senior citizens live with at least one chronic condition, and 67% have two or more, at an annual cost to the National Health Service exceeding €66 billion.

Traditional Limits

Disease-specific prevention has shown notable results. For example, statins lower the risk for composite cardiovascular events by 28% in primary prevention.

But the authors emphasized significant limitations: “Disease-focused approaches to prevent and treat conditions do not address age-related health issues such as fatigue, mobility limitations, and frailty that are common even in the absence of overt disease.”

Frailty illustrates this gap. In the Cardiovascular Health Study, which followed more than 5200 adults for over 30 years, 16% were frailer than expected based on their comorbidities. “After adjusting for comorbidity count, the frailest group experienced 2-3 fewer years of disability-free life compared with those who were not frail,” the authors wrote. 

Age is a disproportionate risk factor. During the COVID-19 pandemic, the mortality rate was seven times higher in those aged 85 years or older (1.6%) than in those aged 65-74 years (0.2%). 

Multimorbidity also rises sharply with age, and “the incidence of developing a third disease among those with two chronic medical conditions is 5.2% among those aged 50-59 years and 16% in those aged 70-79 years,” the authors wrote.

The authors emphasized that single-disease paradigms fail to account for age as the strongest determinant of risk for many diseases, including coronary heart disease, cancer, chronic obstructive pulmonary disease, stroke, dementia, and chronic kidney disease.

Biologic Age

The geroscience hypothesis holds that biologic aging is a process distinct from chronologic aging.

Biologic age quantifies how much a person’s physiology deviates from what would be expected of their chronologic age. For example, “a 50-year-old woman with a maximal oxygen consumption of 32 mL/kg/min, typical of women 10 years younger, would have a biologic age of 40 years,” the authors noted.

Age advancement, defined as the difference between biologic and chronologic age, predicts mortality and other age-related outcomes independently of chronologic age. For example, “an individual with a biologic age 8.3 years older than their chronologic age, based on DNA methylation, had a 2.2-fold higher hazard of death than a person with a similar chronologic age.”

Survivors of childhood cancer also show accelerated biologic aging: “At an average age of 35 years, survivors were biologically 2.2-6.5 years older than age- and sex-matched controls using seven different approaches based on physiologic measures or DNA methylation.”

Cellular Pathways

Biologists specializing in aging have identified cellular pathways that influence lifespan, defined as the total length of life, and health span, defined as the length of life spent free from disease. These pathways involve multiple aspects of cellular physiology, including the accumulation of somatic DNA variations and the regulation and accuracy of DNA transcription.

Regulation includes the maintenance of telomeres and regions of repetitive DNA sequences at the ends of chromosomes that shorten with replication. When telomeres are too short, DNA replication cannot occur. Methylation of DNA bases and other epigenetic changes can alter gene transcription with age.

Maintaining protein structure and function, or protein homeostasis, is strongly associated with aging. In particular, autophagy removes damaged intracellular proteins. Other pathways are related to nutrient sensing, such as signaling induced by amino acids, insulin, or insulin-like growth factor 1, sustaining stem cell populations, and preserving mitochondrial function.

Variations in mitochondrial DNA accumulate with age. One genetic variant, m.3243A>G, is linked to inherited mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode syndrome.

In a cohort of 789 adults aged 70-80 years, approximately 33% carried this variant in 6%-19% of their leukocyte mitochondrial DNA. These individuals showed slower performance, greater arterial stiffness, and reduced grip strength.

Participants with a higher abundance of this variant had increased 17-year mortality rates from dementia and stroke compared with those with the lowest abundance.

Caloric Restriction

Caloric restriction is the most extensively studied intervention in geroscience. 

The authors reported important results: “In one strain of mice, a 20% caloric restriction increased median survival from 785 to 1096 days in females (40%) and from 807 to 999 days (24%) in males.”

The CALERIE trial provided the first evidence of this in humans. The CALERIE trial randomized 218 adults without obesity, aged 21-51 years, to a 2-year intervention comparing caloric restriction with no caloric restriction. The results showed significant cellular changes: Caloric restriction upregulated autophagy and DNA repair and downregulated the inflammatory response, as measured by rank-based pathway enrichment analysis. Participants in the restriction group aged 0.6 years less over the 24 months of the study than participants with no caloric restriction.

Incretin therapies such as semaglutide and tirzepatide offer durable caloric restriction surpassing behavioral interventions and significantly reducing clinical risks in adults with or without type 2 diabetes. Semaglutide (2.4 mg/wk) achieved 14.9% weight loss over 68 weeks. These therapies also lower cardiovascular events by 20% and all-cause mortality by 19%.

Metformin

The review also focuses on metformin, a biguanide and first-line treatment for type 2 diabetes, which may slow age-related biologic processes through its effects on multiple aging pathways.

“Metformin inhibits mitochondrial complex I, which increases AMPK [adenosine monophosphate-activated protein kinase] activity, thereby inhibiting mTOR complex 1 and activating peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These actions enhance autophagy and mitochondrial biogenesis.”

Observational data suggest broad benefits. Among 5528 Veterans Affairs patients with type 2 diabetes, metformin users had a lower incidence of neurodegenerative diseases, including dementia, Parkinson’s disease, Huntington’s disease, and mild cognitive impairment compared with nonusers (11.48 vs 25.45 per 1000 person-years).

Among patients with type 2 diabetes hospitalized with COVID-19 infection, metformin use was associated with a lower 28-day mortality rate (16.0% vs 23.6%). But the authors noted that “Studies of the effects of metformin on patients with diabetes and prediabetes have had inconsistent results,” highlighting the need for studies designed to measure aging-related outcomes.

Rapamycin

Rapamycin, developed to prevent transplant rejection, has shown antiaging effects by acting on mTOR, a regulatory component of the cellular nutrient-sensing pathway. “Reducing mTOR activity increases cellular autophagy,” the authors noted.

“Inhibition of mTORC1 [mTOR complex 1] by rapamycin increased lifespan in multiple model organisms, including mice, even when treatment began at 20 months of age.”

Human evidence is promising but limited. “In a clinical trial of 218 adults aged 65 years or older, 6 weeks of everolimus at 0.5 mg daily or 5 mg weekly was safe and significantly improved the response to influenza vaccination compared with placebo.”

The authors noted that “Lower intermittent doses may improve aging-related biologic pathways while producing fewer adverse effects.”

Senescent Cells

Senolytic drugs are among the most novel geroscience strategies.

“Senescent cells no longer divide, resist apoptosis, and secrete inflammatory cytokines, chemokines, proteases, and other substances collectively known as the senescence-associated secretory phenotype,” the authors explained.

The accumulation of these cells has been documented. Senescent cells accumulate with age.

In a survey of senescent cell markers with age in human tissues, the concentration of kidney cells expressing the senescence marker p21 was 1% in five older donors aged 71-79 years, compared with less than 0.2% in five younger donors aged 19-30 years.

In preclinical studies, eliminating p16-positive cells with AP20187, which induced apoptosis in genetically modified mice expressing p16, increased the median lifespan by up to 27% (from 624 to 793 days) and reduced cancer mortality, delayed cataract formation, and enhanced spontaneous physical activity.

Early clinical trials have shown that this strategy is safe and that senolytic treatment reduces the number of cells expressing p16 and p21, two senescence markers.

Regulatory Hurdles

According to the authors, a significant obstacle to the development of effective prevention strategies is the current regulations. “The FDA does not recognize slowing aging or reducing aging-related conditions, such as sarcopenia or mobility limitation, as approved indications.” 

The authors emphasized that “evaluating approved drugs for age-modifying effects will require broad inclusion criteria, alternative dosing regimens, and longer study durations than those used to establish therapeutic efficacy for their original indications. If multiple clinical trials, including those testing potential indications such as peripheral artery disease, heart failure, or osteoporosis, collect these outcomes, response patterns may be identified to guide future studies with measures more directly linked to specific aging-related biologic targets.” The authors also cautioned about the limitations: “This review had several limitations. First, it was not a systematic review, and the quality of the included evidence was not formally assessed. Second, geroscience is a rapidly evolving field, and relevant references may have been missed.”

Conclusion

Despite these limitations, the authors concluded that “therapies that target aging biology, including caloric restriction, metformin, senolytics, and rapalogs, may slow disease development and progression as well as functional decline in humans.”

This represents a fundamental paradigm shift. Instead of waiting for specific diseases to develop and then treating them individually using disease-specific approaches, geroscience proposes modifying the fundamental biological processes that increase susceptibility to age-related comorbidities.

Therapies that target the biology of aging could not only extend lifespan but, more importantly, improve the “health span” of the years lived in good health without disability or chronic disease. In today’s era of rapid population aging, these strategies could help turn aging from a problem to an opportunity, moving beyond the limits of traditional approaches.

This story was translated from Univadis Italy.

Clearing Zombie Cells Eases Back Pain

 Let's relate this to brain recovery and see if our incompetent stroke medical 'professionals' can understand why to research this! 9 years of incompetence already! WAY TO GO; KEEP UP THE GOOD WORK!

“Zombie” Aging Cells May Speed Up Brain Decline October 2024

senescent cells (8 posts to January 2016)

 Since nothing will occur your children and grandchildren will suffer the consequences of such incompetence!

Send me hate mail on this: oc1dean@gmail.com. I'll print your complete statement with your name and my response in my blog. Or are you afraid to engage with my stroke-addled mind? No excuses are allowed! You're medically trained; it should be simple to precisely state

EXACTLY WHAT YOU ARE DOING that is competent in getting to 100% RECOVERY  with NO EXCUSES! Your definition of competence in stroke is obviously much lower than stroke survivors' definition of your competence! Swearing at me is allowed, I'll return the favor. Don't even attempt to use the excuse that brain research is hard.

The latest here:

Clearing Zombie Cells Eases Back Pain

Summary: A new preclinical study has found that two drugs—o-Vanillin and RG-7112—can clear “zombie cells” from spinal discs, potentially treating the root cause of chronic low back pain. These senescent cells accumulate with age or injury and cause inflammation, pain, and tissue damage.

When administered orally to mice, the drugs reduced inflammation, relieved pain, and even reversed disc damage, with the greatest benefits seen when both drugs were combined. This groundbreaking approach could transform treatment for millions with chronic back pain by targeting the source, not just the symptoms.

Key Facts:

• Root Cause Targeted: Zombie-like senescent cells drive inflammation in spinal discs.
• Dual Drug Effect: o-Vanillin and RG-7112 worked best when used together.
• Oral Success: Drugs delivered by mouth reached hard-to-access spinal discs and reversed damage.

Source: McGill University

In a preclinical study led by McGill University researchers, two drugs targeting “zombie cells” have been shown to treat the underlying cause of chronic low back pain. The condition affects millions of people worldwide.

Current treatments manage symptoms through painkillers or surgery, without addressing the root cause.

The results offer some of the first evidence that o-Vanillin can clear out zombie cells. Credit: Neuroscience News

“Our findings are exciting because it suggests we might be able to treat back pain in a completely new way, by removing the cells driving the problem, not just masking the pain,” said senior author Lisbet Haglund, a Professor in McGill’s Department of Surgery and Co-director of the Orthopaedic Research Laboratory at the Montreal General Hospital (MUHC).

The work was conducted by McGill’s Alan Edwards Centre for Research on Pain at the Montreal General Hospital, part of the MUHC.

Treating pain at the source

Senescent cells, often called zombie cells, build up in the spinal discs as people age or when discs are damaged. Instead of dying off like normal cells, these aging cells linger and cause inflammation, pain and damage to the spine.

To explore a potential solution, the research team administered two drugs orally to mice: o-Vanillin, a natural compound, and RG-7112, an FDA-approved cancer drug. They were administered together as well as separately.

They found the drugs could clear zombie cells from the spine, reduce pain and inflammation, and slow or even reverse damage to spinal discs after eight weeks of treatment. Each of the drugs had a beneficial effect, but the impact was greatest when they were administered together.

“We were surprised that an oral treatment could reach the spinal discs, which are hard to access and present a major hurdle in treating back pain,” said Haglund. “The big question now is whether these drugs can have the same effect in humans.”

A natural compound’s surprising potential

Notably, o-Vanillin wasn’t originally intended to be part of the study and was included almost by chance. Haglund explained that while testing other drugs, her team decided to add the compound, derived from turmeric and known for its anti-inflammatory properties, to see whether it might be effective in this situation.

The results offer some of the first evidence that o-Vanillin can clear out zombie cells. Analogs of RG-7112 are known to do this in osteoarthritis and cancer research, but had not been used to treat back pain.

Looking ahead, Haglund’s team will work to improve o-Vanillin’s structure to help it stay in the body longer to become even more effective. They believe these drugs have the potential to treat other age-related diseases driven by senescent cells, such as arthritis or osteoporosis.

(So your researchers will need to figure out how to use nanocarriers to deliver this past the blood brain barrier. Or maybe nasal delivery. If they don't know how to deliver drugs to the brain, they are totally fucking incompetent!

nanocarriers (15 posts to March 2012)

nasal delivery (7 posts to December 2017))

About the study

“Senolytic Treatment for Low Back Pain” by Matthew Mannarino, Hosni Cherif and Lisbet Haglund et al., was published in Science Advances.

Funding: The study was funded by the Canadian Institutes of Health Research, The Arthritis Society, Le Réseau de Recherche en Santé Buccodentaire et Osseuse and the Louise and Alan Edwards Foundation.

Senolytics: Zombie Cells, Longevity, and What’s Possible

 

 Hasn't your competent? doctor already gotten human testing done for all this earlier research on senescent cells? NO? So you DON'T have a functioning stroke doctor, do you?

senescent cells (9 posts to January 2016)

And for your entertainment as your struggle to recover, hopefully you're walking better than zombies.

Can we study zombies to understand stroke deficits? October 2011

The latest here:

Senolytics: Zombie Cells, Longevity, and What’s Possible

For many people, living longer brings health challenges: Osteoporosis, diabetes, Alzheimer’s disease. And of course, zombie cells.

The technical term is senescent cells. They’re damaged and unable to repair themselves. They’re also more likely to linger in the body as we age — like zombies — secreting inflammatory molecules that can hasten our decline.

“They have this very robust secretory phenotype,” said Nathan K. LeBrasseur, PhD, director of the Robert and Arlene Kogod Center on Aging at Mayo Clinic. “They drive things such as impaired tissue regeneration, fibrosis, degeneration, inflammation — a lot of the conditions that are clearly central to age-related diseases. And that’s what’s exciting about these cells as therapeutic targets.”

That is, targets for senolytics, the still-experimental drugs and supplements that eliminate senescent cells or tamp down their ill effects. Cancer is a particularly promising research area for senolytics (some existing chemo drugs have senolytic properties).

Proponents like LeBrasseur aren’t preaching about extreme longevity, but the health span/lifespan argument. They speak in practical terms about making life easier for people as they get older.

“We’re really not interested in making drugs to help us live until we’re 120 and feel like we’re 120,” he said. “If we have no effect on lifespan, that’s perfectly fine, but let’s increase the number of active and productive years that are not overly burdened by disease and disability.”

It sounds tantalizingly possible — and sort of gimmicky. The internet teems with products claiming to be “antiaging” senolytics. But the internet teems with a lot of things.

What’s real about senolytics as a future therapeutic option and how might they truly affect how people age?

The State of Senolytics

Since the first senolytics were discovered in 2015, much of the promising research has been in mice. Some early senolytics, like navitoclax (ABT-263) and ABT-737, have stalled out (they ended up killing platelets in people and speeding up ovarian aging in older female mice). So far, the most effective senolytics are existing chemotherapy drugs.

“We don’t have this medicine cabinet full of options to take into humans,” LeBrasseur said. “There’s a couple of repurposed drugs that are being tried and trialed.”

Here’s where things stand now. Roughly 20 clinical trials are underway, and at least 10 more are planned or have published some results. There are trials on senolytics for osteoarthritis, COVID-19, Alzheimer’s, and Parkinson’s diseases, according to Paul Robbins, PhD, associate director of the Masonic Institute on the Biology of Aging and Metabolism and a professor at the University of Minnesota. Another trial is treating grafts from older donors with senolytics before transplant. Amid these investigations, emerging evidence shows that senolytics can reduce senescence in humans and provide other benefits.

Robbins points to the results of a “very positive trial” led by Unity Biotechnology, published last year. It showed that a senolytic called foselutoclax benefited people with advanced diabetic macular edema. A single injection in the back of the eye improved their sight, especially in the dark, for at least 6 months. The drug works by inhibiting a protein that regulates cell death, leading to a removal of senescent cells that researchers believe spurs healing in the eye.

Another standout senolytic is known as D+Q, a combination of dasatinib (a US Food and Drug Administration [FDA]–-approved chemotherapy drug) and quercetin (a flavonoid found naturally in many foods). Dasatinib targets certain classes of receptors on the surface of some — but not all — senescent cells, triggering “a natural death process,” LeBrasseur explained. “It’s kind of flipping off a light switch in the cell, so it goes to sleep.”

Research published in 2017 and 2018 found that D+Q improved bone density, lifespan, and physical function in older mice. Co-author Ming Xu, PhD, an associate professor at the University of Minnesota, said those studies “laid the foundation for a number of ongoing clinical trials.”

A phase 1 clinical trial showed that intermittent doses of D+Q improved physical function in 12 older people with idiopathic pulmonary fibrosis, a serious lung disease. And a phase 2 trial in 60 healthy postmenopausal women showed that D+Q boosted formation of new bone tissue, but did not reduce bone resorption (the breakdown and removal of old bone tissue).

Importantly, 10 women with the highest baseline biomarkers for senescent cell burden benefited more — with increases in bone formation, less bone resorption, and enhanced wrist bone mineral density.

That kind of finding can help move the needle, according to LeBrasseur. “One challenge in our field is, how do we select individuals who best respond to these interventions?” he said.

Major Roadblock: The Heterogeneity of Senescent Cells

Senescent cells are extremely heterogeneous, and researchers are still determining what that looks like in a broad sense. The SenNet Consortium, funded by the National Institutes of Health Common Fund, is a vast research network striving to spatially map senescent cells in human tissues.

“It’s turned out to be a monster of a task,” said Robbins. “A senescent cell in the kidney is different than the liver, which is different than the brain.”

Even within the same tissues, there can be numerous distinct subpopulations of senescent cells, according to Xu. And totally different cells might share senescence features. Take p16 and p21, two proteins identified as drivers of cell senescence. Even if some cells highly express p16, whereas others highly express p21, they might have senescent features in common, causing a drug to clear cells that shouldn’t be cleared.

“The problem is, we can’t really differentiate between them. We don’t have good markers that separate them,” Robbins said. “But it seems that functionally, if you treat with senolytics in an old animal, that’s beneficial. There’s conflicting data in young animals about whether there’s good or bad effects of trying to clear these cells.”

Adding to the mystery: Not all senescent cells are bad. In fact, “senescence has sort of evolved as an anticancer mechanism,” Robbins said. Some senescent cells are linked to tumor suppression, wound healing, and tissue repair. Generally speaking, the immune system clears these cells not long after detecting them but immune dysfunction and other factors like old age may prevent that and the cells can become pro-inflammatory and not so friendly.

Senescent cells are damaged and unable to repair themselves, but not so damaged that they self-destruct — a process called apoptosis. For reasons scientists don’t fully understand, senescent cells upregulate pathways that keep them from dying. It could be that the body has an “immune memory” against senescent cells.

“There must be an advantage to having the cells survive and then have the immune system kill them,” Robbins said.

To that end, many researchers are developing immunotherapies to target and clear senescent cells. A team at Memorial Sloan Kettering Cancer Center and Cold Spring Harbor Laboratory showed that engineered immune cells used for treating blood cancers had a senolytic effect in aging mice. Their metabolic function improved when CAR T cells eliminated urokinase plasminogen activator receptor, a senescent-associated protein. The treatment also protected against metabolic decline in younger mice.

A Senolytic ‘Cocktail’

Chemotherapy drugs, senolytic cell inhibitors, and immunotherapy are just some of the emerging senolytic options. Robbins and his colleagues are working on a senolytic lipid, a senolytic RNA, and senolytic natural compounds. They’re part of a phase 2 clinical trial investigating if the senolytic drug Fisetin (a flavonoid found in many fruits and vegetables) can thwart severe COVID-19.

All these senolytics “seem to target different classes of senescent cells,” Robbins said. And different senescent cells could contribute to a single disease. That’s why a “cocktail” of senolytics could ultimately emerge, he said. Your cocktail could depend on whether “you’re just trying to maintain your health vs trying to treat Alzheimer’s vs trying to treat other conditions.”

Felix Wong, PhD, co-founder of biotechnology company Integrated Biosciences, agrees. “There’s not going to be just one blockbuster senolytic, but perhaps many multiple different senolytics,” Wong said.

Two years ago, Wong’s team used deep learning to discover three potential senolytic compounds from a database of 800,000 molecules. They trained a graph neural network, a type of artificial intelligence model, to make predictions of senolytic activity based on chemical structure alone. When injected into aged mice, the compounds decreased the accumulation of senescent cells. Promising — but still a long way from your medicine cabinet. Wong said that Integrated Biosciences is still examining which disease models the compounds might be efficacious in.

“The FDA doesn’t recognize aging as a disease, so you’ll have to go after a specific indication,” Wong said.

That’s true, at least for now. Last December, Advanced Research Projects Agency for Health (ARPA H), an agency within the US Department of Health and Human Services, launched Proactive Solutions for Prolonging Resilience (PROSPR). The initiative could lead to a measurement of “intrinsic capacity” — a potential yardstick for testing drugs that target aging more broadly — according to LeBrasseur. Even so, he suggests it might be another decade before the field can say with confidence that a senolytic works.

What About Nature’s Senolytic?

In the meantime, of course, there’s exercise. LeBrasseur’s research has shown that higher levels of “habitual physical activity” — daily activities like walking and getting up out of your chair that make you “a little less sedentary” — is associated with lower biomarkers of senescence in adults in their 70s and 80s.

“Exercise can prevent senescence from occurring,” LeBrasseur said. “And there’s a lot of favorable data to show exercise can help optimize immune health and function, creating healthier environments and tissues for immune cells to recognize, target, and eliminate senescent cells.”

Wong is still hoping for a shift in thinking about the ability to treat aging. He pointed out that glucagon-like peptide 1 (GLP-1) agonists show benefits well beyond obesity, treating neurodegenerative and kidney diseases associated with aging, for instance.

“The battle call is out there. We all know that GLP-1 agonists are broadly, quote-unquote, antiaging, and I think that represents a paradigm shift,” Wong said. “There’s a growing appreciation for the fact that we can, using therapeutic interventions, actually move the needle across different age-related diseases.”

“Zombie” Aging Cells May Speed Up Brain Decline

 Hasn't your competent? doctor already gotten human testing done for all this earlier research on senescent cells? NO? So you DON'T have a functioning stroke doctor, do you?

senescent cells (8 posts to January 2016)

“Zombie” Aging Cells May Speed Up Brain Decline

Summary: Recent research shows that senescent, or “zombie,” skin cells may accelerate aging throughout the body. When transplanted into a preclinical model, these cells caused senescence to spread to other organs, impairing muscle function and brain health.

This discovery suggests that skin aging could drive broader systemic aging, offering new insights into the connection between skin conditions and overall decline. The study supports anti-aging strategies that address both physical and cognitive health by targeting senescent cells.

Key Facts:

• Senescent skin cells can accelerate aging in other organs and systems.
• The spread of these cells impairs muscle function and brain health.
• The research supports anti-aging approaches that target senescent cells in the skin.

Source: Mayo Clinic

Mayo Clinic researchers have found that senescent cells—non-dividing “zombie” cells—accumulate in the skin as people age and may influence aging in other parts of the body.

Their recent study revealed that transplanting senescent skin cells into a preclinical model revealed that they not only caused that senescence to spread to other tissues but also accelerated physical decline, impaired muscle function and adversely affected brain health. This discovery indicates that senescent cells in the skin could drive broader, systemic aging.

This research also offers support for anti-aging strategies that aim to keep both the body and mind healthier for longer. Credit: Neuroscience News

“This discovery is significant because it suggests that senescent cells in the skin—an organ not typically associated with aging, beyond wrinkles—might be driving broader, systemic aging processes.

“These findings could also help explain the link between skin conditions and cognitive decline, offering potential new pathways for addressing both physical and mental deterioration as we age,” says Mayo Clinic researcher João Passos, Ph.D., who is one of the lead authors on the study, published in Aging Cell.

This research also offers support for anti-aging strategies that aim to keep both the body and mind healthier for longer.

“This study suggests that skin senescence may accelerate aging in other organs, highlighting the importance of preventing factors like sun exposure, smoking, alcohol and poor diet that contribute to premature skin aging,” says Ana Catarina Franco, the study’s first author and Mayo Clinic visiting graduate student.

The researchers aim to investigate whether senolytic drugs, originally developed at Mayo Clinic and shown to eliminate senescent cells among people with a high number of senescent cells, can improve overall health when applied topically to the skin.

They also plan to do more research to try to understand the mechanisms by which senescent cells may spread from the skin to other organs.

About this brain aging research news

Author: Ana Catarina Franco
Source: Mayo Clinic
Contact: Ana Catarina Franco – Mayo Clinic
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Senescent cell transplantation into the skin induces age‐related peripheral dysfunction and cognitive decline” by Ana Catarina Franco et al. Aging Cell

Phase I trial of senolytic therapy shows promise in Alzheimer's disease

You might need this. Is your competent doctor closely following this? 

Your risk of dementia, has your doctor told you of this?  Your doctor is responsible for preventing this!

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.`    

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

The latest here:

Phase I trial of senolytic therapy shows promise in Alzheimer's disease

Alzheimer's disease is the most common cause of dementia that affects more than 6.5 million Americans, according to the Alzheimer's Association. To find effective treatments and slow the progression of this debilitating disease, researchers have made much progress in developing new drugs that target beta-amyloid plaques, one of the hallmarks of Alzheimer's disease.

Beta-amyloid plaques are accumulations of brain protein fragments, which can impact cognition. However, these recent drugs have only yielded modest results.

Now, scientists at Wake Forest University School of Medicine are reporting results from a Phase I trial in another area of promising research-;cellular senescence.

The findings appear online today in Nature Medicine.

Senescent cells are old, sick cells that cannot properly repair themselves and don't die off when they should. Instead, they function abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues throughout the body contributing to the aging process, neurocognitive decline and cancer.

In 2018, we found evidence of senescent cells in human Alzheimer's disease. In mouse models, we also found that they contribute to brain cell loss, inflammation and memory impairment."

Miranda Orr, Ph.D., associate professor of gerontology and geriatric medicine at Wake Forest University School of Medicine

Researchers repurposed a U.S. Food and Drug Administration-approved drug designed to clear cancer cells (dasatinib) in combination with a flavonoid, a plant-derived antioxidant (quercetin).

"Our previous research has shown that the combination of these two drugs target senescent cells and allow them to die," Orr said. "We know that they cleared senescent brain cells in Alzheimer's disease mouse models, and they had already been shown to be safe in patients with other ailments."

For the current study, which was co-led by Mitzi Gonzales, Ph.D., of The University of Texas Health Science Center at San Antonio, the research team enrolled five participants aged 65 and older with symptoms of early-stage Alzheimer's disease. Participants received oral dasatinib plus quercetin over two consecutive days, followed by two weeks of no drugs. The cycle repeated six times for a total of 12 weeks.

"Our primary goal was to determine whether the medicines penetrated the central nervous system," Orr said. "We collected samples of patients' cerebrospinal fluid (CSF) before the first dose of medicine was given and after the last dose of medicine was given."

Antibodies eBook Compilation of the top interviews, articles, and news in the last year. Download the latest edition

The research team also collected data on the safety and efficacy of the two drugs by monitoring side effects. They assessed biomarkers of senescence in CSF and blood, and also evaluated patients' cognition and brain images before treatment and after they completed the 12-week study.

They found that both dasatinib and quercetin levels increased in the blood, and dasatinib was detected in the CSF in four subjects. Quercetin was not detected in the CSF of any participants.

"We also determined that the treatment was safe, feasible and well-tolerated," Orr said. "There were no significant changes in brain function as determined by assessing memory and brain imaging to provide additional evidence that it is a safe therapy to evaluate further."

Researchers also saw evidence to suggest that the combination therapy cleared amyloid from the brain and lowered inflammation in the blood.

"However, we shouldn't over-interpret these results," Orr said. "There was a small number of people enrolled, there was no placebo arm to compare results."

Researchers also noted an increase in inflammation in CSF biomarkers. According to Orr, one possible explanation is a transient increase in inflammation when senescent cells are cleared. This increase could also be a marker of senescent cells dying or could potentially indicate inflammation associated with the treatment.

"We will need to monitor this closely in our next trial," said Orr, whose cellular senescence research is currently featured in a special issue of National Geographic focused on aging.

"Dr. Orr's research is a critical part of this pivotal moment in Alzheimer's research as the focus shifts from amyloid and tau, the classic disease hallmarks, toward how the biology of aging underlies the disease," said Howard Fillit, M.D., co-founder and chief science officer at the Alzheimer's Drug Discovery Foundation (ADDF). "Aging is the leading risk factor for Alzheimer's, and it is important that the field explores new approaches for developing therapeutics, like senolytics, that target biological aging. Alzheimer's is a multifaceted disease, and similar to cancer, we will need multiple treatment options that can be combined and personalized to improve the outlook for millions of patients living with Alzheimer's."

Orr's research team is in the process of a larger $3 million, Phase II clinical trial funded by the ADDF to test the effects of clearing senescent cells with the combination therapy.

"We can confidently move forward with a larger study population and placebo arm knowing that the treatment is safe," Orr said. "We will also look forward to learning more about how the treatment may impact Alzheimer's disease biomarkers."

Source:

Atrium Health Wake Forest Baptist

Journal reference:

Gonzales, M. M., et al. (2023). Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nature Medicine. doi.org/10.1038/s41591-023-02543-w.

Biological age is a better health indicator than the number of years you’ve lived—here's how to measure it

Except that the article tells us nothing useful on measuring it.

Biological age is a better health indicator than the number of years you’ve lived—here's how to measure it

 

Do you ever wake up some days and think, “When I was younger, I could survive on just four hours of sleep, but now it seems like I need 10”? Or have you ever walked out of the gym and “felt” your knees?

Almost everyone experiences these kinds of signs of aging. But there are some people who seem to defy their age. The late U.S. Supreme Court Justice Ruth Bader Ginsberg stayed on the bench until her death at age 87. The “Great British Bake Off” judge Mary Berry, now in her 80s, continues to inspire people all over the world to bake and enjoy life. And actor Paul Rudd was named People magazine’s “Sexiest Man Alive” in 2021 at age 52 while still looking like he’s in his 30s. Is age just a number then?

Researchers have focused a lot of attention on understanding the causes and risk factors of age-related diseases like Alzheimer’s, dementia, osteoporosis and cancer. But many ignore the major risk factor for all of these diseases: aging itself. More than any individual risk factor such as smoking or lack of exercise, the number of years you’ve lived predicts onset of disease. Indeed, aging increases the risk of multiple chronic diseases by up to a thousandfold.

However, no two people age the same. Although age is the principal risk factor for several chronic diseases, it is an unreliable indicator of how quickly your body will decline or how susceptible you are to age-related disease. This is because there is a difference between your chronological age, or the number of years you’ve been alive, and your biological age – your physical and functional ability.

I am a scientist interested in redefining “age.” Instead of benchmarking chronological age, my lab is invested in measuring biological age. Biological age is a more accurate measure of healthspan, or years lived in good health, than chronological age, and doesn’t directly correlate with wrinkles and gray hairs. Rapid agers experience a faster rate of functional deterioration relative to their chronological age.

My grandmother, who lived to be 83 but was bedridden and could not remember who I was for the last few years of her life, was a rapid ager. My grandfather, on the other hand, also lived until he was 83, but he was active, functional and even did my homework with me until he passed away – he was a healthy ager.

With the unprecedented growth of the world’s aging population, I believe that figuring out ways to measure biological age and how to maintain or delay its advance is critical not only for individual health, but also for the social, political and economic health of our society. Detecting rapid agers early on presents an opportunity to delay, change or even reverse the trajectory of biological aging.

Genetics and biological age
Biological aging is multifaceted. It arises from a complex mix of genetic traits and is influenced by factors like microbiome composition, environment, lifestyle, stress, diet and exercise.

Genetics were once thought to have no influence on aging or longevity. However, in the early 1990s, researchers reported the first studies identifying genes that were able to extend the lifespan of a small roundworm. Since then, multiple observations support the influence of genetics on aging.

For example, children of long-lived parents and even those with long-lived siblings tend to live longer. Researchers have also identified multiple genes that influence longevity and play a role in resilience and protection from stress. These include genes that repair DNA, protect cells from free radicals and regulate fat levels.

However, it is clear from studies in identical twins – who share the same genes but not the same exact lifespans – that genes are not the only factor that influences aging. In fact, genes probably account for only 20% to 30% of biological age. This suggests that other parameters can strongly influence biological aging.



Environmental and lifestyle effects
Researchers have found that environmental and lifestyle factors heavily influence biological age, including social connectedness, sleeping habits, water consumption, exercise and diet.

Social connectedness is essential for well-being throughout life. But social connections can be challenging to maintain over time due to loss of family and friends, depression, chronic illness or other factors. Several studies have reported a strong link between social isolation and increased stress, morbidity and mortality.

Similarly, diet and exercise are strong influencers of biological age. Blue zones, which are areas around the world where people live long lives, attribute their successful aging to diet, exercise and social connectedness. Mostly plant-based meals and spurts of activity throughout the day are well-known “secrets” of healthspan and longevity. Although newer studies on the effects of diet interventions such as intermittent fasting and time-restricted feeding on longevity have not been rigorously tested, they do show multiple health benefits, including better glucose and insulin regulation

While genetics is difficult to control, diet and exercise can be modified to delay biological aging.

How to measure biological age
Currently, there is no effective test to predict an individual’s health trajectory early enough in life in order to intervene and improve quality of life with age. Scientists are interested in identifying a molecule that is sensitive and specific enough to serve as a unique fingerprint for biological age.

Considering the health and resilience of the individual instead of focusing solely on disease state is important in discussions on biological age. Resilience is the state of adapting and bouncing back from a health challenge and is often more predictive of functional health. A molecular aging fingerprint may provide a tool to help identify people who are less resilient and require more aggressive monitoring and early intervention to preserve their health and help reduce gender, racial and ethnic health disparities.

There are several promising molecular markers that may serve as biological age fingerprints.

One of these markers are epigenetic clocks. Epigenetics are chemical modifications of DNA that control gene function. Several scientists have found that DNA can get “marked” by methyl groups in a pattern that changes with age and could potentially act as a readout for aging.

It is important to note, however, that while epigenetic clocks have been valuable in predicting chronological age, they do not equate to biological age. In addition, it is unclear how these epigenetic marks work or how they contribute to aging.

Another well-regarded marker of biological age is the build-up of dysfunctional cells called senescent or zombie cells. Cells become senescent when they experience multiple types of stress and become so damaged that they cannot divide anymore, releasing molecules that cause chronic low-grade inflammation and disease.

Animal studies have shown that getting rid of these cells can improve healthspan. However, what clearly defines senescent cells in humans is still unknown, making them challenging to track as a measure of biological age.

Lastly, the body releases unique metabolites, or chemical fingerprints, as byproducts of normal metabolism. These metabolites play a dynamic and direct role in physiological regulation and can inform functional health. My lab and others are figuring out the exact makeup of these chemicals in order to figure out which can best measure biological age. A lot of work still remains on not only identifying these metabolites, but also understanding how they affect biological age.

People have long sought a fountain of youth. Whether such an elixir exists is still unknown. But research is starting to show that delaying biological age may be one way to live healthier, fuller lives.

Aditi Gurkar, Assistant Professor of Geriatric Medicine, University of Pittsburgh

This article is republished from The Conversation under a Creative Commons license. Read the original article.

This story was originally featured on Fortune.com

'Zombie cells' hold clues to spinal cord injury repair

 Will this do the same for stroke? WHOM do we ask to do the followup research? Specific names only. With NO LEADERSHIP AND NO STRATEGY NOTHING WILL BE DONE.

 

'Zombie cells' hold clues to spinal cord injury repair

by Instituto de Medicina Molecular

The image represents a transversal cross-section of a mouse spinal cord. Neuronal cell bodies are represented in light blue delineating the butterfly shape characteristic of the gray matter, while glial projections are represented in orange-red. Credit: Diogo Paramos-de-Carvalho

Mammals have a poor ability to recover after a spinal cord injury, which can result in paralysis. A main reason for this is the formation of a complex scar associated with chronic inflammation that produces a cellular microenvironment blocking tissue repair. Now, a research team led by Leonor Saude, group leader at Instituto de Medicina Molecular Joao Lobo Antunes (iMM; Portugal) and Professor at Faculdade de Medicina da Universidade de Lisboa, have shown that the administration of drugs that target specific cellular components of this scar improve functional recovery after injury. The results now published in the scientific journal Cell Reports set the basis for a new promising therapeutic strategy not only for spinal cord injuries, but potentially for other organs that lack regenerative competence.

This study was performed at iMM with collaboration from researchers at CEDOC NOVA Medical School and was funded by "la Caixa" Foundation—CaixaResearch Call and Fundacao para a Ciencia e a Tecnologia (Portugal).

Leonor Saude and her team have been studying spinal cord injury using two different models: zebrafish, which exhibit spinal injury recovery, and mammals, which show poor recovery. The dense scar that forms at the lesion site has been of particular interest. In mammals, upon spinal cord injury, researchers observed that cells start to accumulate at the lesion periphery. But not any cells: "These cells are known as senescent cells. They have specific features and markers and are what we can call 'zombie cells', where growth and division is interrupted, but where the normal cell death program is not activated," explains Leonor Saude.

"While in zebrafish, the accumulation of these cells at the injury periphery is cleared out over time, in mammals, these cells persist and are important components of the dense scar observed. Because senescent cells have specific molecular markers, there are specific drugs that could be tested in this context," says Diogo Paramos-de-Carvalho, first author of the study. "With the administration of different senolytic drugs, that specifically target these senescent cells, we have observed a progressive decrease of these cells, a decrease in the scar extension and lower levels of inflammation due to a decreased secretion of pro-fibrotic and pro-inflammatory factors. The observed changes at the molecular level underlie the improved locomotor, sensory and bladder functions that we have also found," explains Isaura Martins, also first author of the study.

"Although we are still far from healing spinal cord injuries in humans, we are learning more about the molecular signatures of these lesions and these new promising results can open new therapeutic strategies that can be applied not only to spinal cord injuries but in other conditions that lack regenerative competence," says Leonor Saude.

 

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

This might just help your recovery from stroke, won't know until human research is accomplished. Your doctor and stroke hospital can once again completely fail at contacting researchers to get clinical trials done.  Of the thousands of research articles I've cited has your stroke hospital done ONE DAMN THING with any of them? Created protocols? Initiated research? Nope? Then you need to start firings with the board of directors. 

 Quotes from the article referencing the research; 'If we can clear senescent cells, then we can probably clear Alzheimer's'. 'Maybe we can remove senescent astrocytes and finally get some headway on Alzheimer's'.

From 'Why Alzheimer's hits older brains' New Scientist, Sept. 29, 2012

Clearance of p16^Ink4a-positive senescent cells delays ageing-associated disorders

• Darren J. Baker,
• Tobias Wijshake,
• Tamar Tchkonia,
• Nathan K. LeBrasseur,
• Bennett G. Childs,
• Bart van de Sluis,
• James L. Kirkland &
• Jan M. van Deursen 

Nature volume 479, pages232–236(2011)Cite this article

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Abstract

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells^1,2. Senescent cells accumulate in various tissues and organs with ageing³ and have been hypothesized to disrupt tissue structure and function because of the components they secrete^4,5. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16^Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16^Ink4a-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16^Ink4a-positive senescent cells upon drug treatment. In tissues—such as adipose tissue, skeletal muscle and eye—in which p16^Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16^Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

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