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New Anti-Aging Combo Boosts Lifespan in Old Male Mice

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“Extending lifespan and healthspan remains a central goal of biomedical research and has been tackled through numerous and diverse approaches.”

As life expectancy increases, there is growing interest not only in extending lifespan but also in improving the quality of those additional years. To address the physical and cognitive decline that often accompanies aging, researchers have explored a variety of strategies. Many of these focus on a single biological factor, such as reducing inflammation or stimulating stem cell activity. However, aging is a complex process involving multiple, interconnected changes in the body.

Recognizing this, researchers at the University of California, Berkeley proposed a more comprehensive approach: targeting multiple aging-related pathways simultaneously. Their study, titled “Sex-specific longitudinal reversal of aging in old frail mice,” was recently featured on the cover of Aging-US (Volume 17, Issue 9).

The Study: A Dual Treatment Using Oxytocin and an Alk5 Inhibitor

In this study, a team led by first author Cameron Kato and corresponding author and Aging-US Editorial Board member Irina M. Conboy tested a combination treatment on very old and frail mice, roughly equivalent in age to 75-year-old humans. The treatment involved two compounds: oxytocin, a hormone that naturally declines with age and is involved in tissue repair and regeneration, and an Alk5 inhibitor, which blocks part of the TGF-β signaling pathway. This pathway often becomes overactive in older individuals, contributing to inflammation and impaired tissue function.

The researchers aimed to determine whether targeting both the declining and overactive systems at the same time would be more effective than addressing just one.

The Results: Distinct Effects in Male and Female Mice

In male mice, the results were notable. Lifespan increased by 14 percent when measured from birth, and by over 70 percent when measured from the start of treatment in old age. These mice also showed improved physical performance, including better endurance, strength, and memory. Even after reaching a certain level of frailty, they continued to live longer than untreated mice, suggesting that the treatment not only prolonged life but also helped maintain function.

In contrast, the same treatment did not improve lifespan or general health in female mice. However, when administered to middle-aged females, the treatment enhanced fertility. This suggests that biological sex and timing may significantly influence how the treatment works.

The Impact: Multi-Target Strategies for Addressing Aging

Although this research was conducted in mice, it adds valuable insight to a growing field focused on coordinated, multi-target approaches to aging. Both oxytocin and Alk5 inhibitors are already being studied or used in clinical settings for other conditions, which means their safety profiles are at least partially understood. This opens the door for future studies exploring whether similar treatments could be applied to human aging.

Future Perspectives and Conclusion

This study presents a promising model for how aging could be addressed through balanced therapeutic strategies. It also highlights the importance of understanding sex-specific responses to treatment. The effectiveness of the therapy in males, and the fertility response in females, point to the need for personalized approaches in future research.

While more studies are necessary to determine whether these findings can be translated to humans, the results suggest that even in later stages of life, it may be possible to improve health and resilience by restoring balance in the body’s signaling systems.

Click here to read the full research paper published in Aging-US.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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How Exosomes Spread Aging Signals and Could Support Anti-Aging Research

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“Senescent cells release a senescence-associated secretory phenotype (SASP), including exosomes that may act as signal transducers between distal tissues, and propagate secondary senescence.”

As the global population grows older, understanding what drives the aging process is becoming increasingly important. Diseases like Alzheimer’s, cardiovascular conditions, and cancer are more common with age, yet many current treatments only manage symptoms rather than addressing the underlying biological causes.

One contributor to aging is the buildup of “senescent” cells—cells that have stopped dividing but do not die. These cells can harm nearby tissues by releasing molecular signals, a process known as secondary senescence.

Scientists have found that senescent cells release tiny particles called exosomes. A research team from The Buck Institute for Research on Aging recently discovered that these exosomes carry aging-related messages through the bloodstream. Their study, titled “Exosomes released from senescent cells and circulatory exosomes isolated from human plasma reveal aging-associated proteomic and lipid signatures,” was featured as the cover article in Aging (Aging-US), Volume 17, Issue 8.

The Study: Exosomes and Aging

The team led by Sandip Kumar Patel, Joanna Bons, and Birgit Schilling from The Buck Institute for Research on Aging focused their study on exosomes—tiny, bubble-like structures released by cells that carry proteins, lipids, and genetic material. These particles can move through the bloodstream and influence distant tissues. 

The researchers wanted to know whether exosomes from senescent cells and from the blood of older adults shared common markers of aging. Since aging cells are spread throughout the body and lack a single clear marker, exosomes could provide a new way to detect their presence through a simple blood test.

To explore this, the team analyzed exosomes from two sources: lab-grown human lung cells that had undergone senescence and blood samples from both young (20–26 years old) and older (65–74 years old) adults. They used high-throughput mass spectrometry.

Results: Exosomes Reveal Signs of Aging

In total, the team identified over 1,300 proteins and 247 lipids within the exosomes. Specifically, 52 proteins appeared in both senescent cells and the blood plasma of older adults, many of which are associated with inflammation and tissue damage. Some examples include Prothrombin, Plasminogen, and Reelin—molecules involved in blood clotting, tissue remodeling, and neural development. Their presence in both aged blood and senescent cells suggest a broader impact of aging on multiple biological systems.

The team also observed significant changes in the lipid content of the exosomes. Lipids that help maintain cell membrane structure were more common in samples from older individuals, while lipids involved in energy storage were less abundant.

In addition, the researchers detected changes in microRNAs—small pieces of genetic material that regulate gene expression. Several microRNAs found in the blood of older adults have already been associated with diseases such as Alzheimer’s and osteoarthritis.

The Impact: Potential for Diagnostics and Anti-Aging Therapies

This study is among the first to directly compare exosomes from senescent cells and human plasma, revealing shared aging-related markers across biological systems.

These particles act like messengers, spreading signals that may accelerate aging in other cells. This supports the concept of secondary senescence—where aging-like behavior is transmitted from senescent cells to healthy ones—suggesting that exosomes may help propagate aging throughout tissues over time.

This work could lead to the development of blood tests that measure biological age more accurately than a person’s chronological age. It might also help clinicians monitor the effectiveness of anti-aging treatments.

Future Perspectives and Conclusion

Although the study involved a small number of human samples, it presents a promising new approach to studying aging. If confirmed in larger studies, the findings could lead to improved diagnostic tools and therapies for age-related diseases.

In the long term, researchers may explore ways to block or modify harmful exosome signals to protect healthy cells from premature aging. These molecular signatures could also support personalized medicine approaches or help track the effectiveness of anti-aging interventions in clinical settings.

Click here to read the full research paper published in Aging (Aging-US).

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Skin Rejuvenation: How Young Blood and Bone Marrow Influence It

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“Heterochronic parabiosis studies illuminated the potential for rejuvenation through blood-borne factors, yet the specific drivers including underlying mechanisms remain largely unknown and until today insights have not been successfully translated to humans.”

A new study published as the cover of Aging (Aging-US) Volume 17, Issue 7, explores how factors in young human blood may affect the biological age of human skin. Researchers from Beiersdorf AG, Research and Development Hamburg in Germany, used a microphysiological co-culture system—a lab-based model simulating human circulation—to test the effects of young versus old blood serum on skin cells. The findings suggest that bone marrow-derived cells play a key role in converting blood-borne signals into effects that support skin rejuvenation.

Understanding Skin Aging and Systemic Influence

As we age, the skin’s ability to regenerate declines, while its biological age increases. This contributes to visible signs of aging and a weakened barrier function. While cosmetic treatments can improve appearance, they rarely target the cellular processes underlying skin aging.

Animal studies have shown that exposure to young blood can promote tissue repair and rejuvenation, likely due to molecules circulating in the bloodstream. However, reproducing these effects in human skin has proven difficult. Applying young serum directly to skin tissue has not produced significant results, indicating that additional cellular interactions may be required.

The Study: A Two-Step Regenerative Protocol

The research team, led by first author Johanna Ritter and corresponding author Elke Grönniger from Beiersdorf AG, developed an innovative in vitro system combining two engineered human tissue models: full-thickness skin and bone marrow. Using the HUMIMIC Chip3plus platform, they created a miniature circulatory system where these tissues could interact through shared culture media.

The study, titled “Systemic factors in young human serum influence in vitro responses of human skin and bone marrow-derived blood cells in a microphysiological co-culture system,” investigated how human serum from young (<30 years) and older (>60 years) donors influenced markers of skin aging over a 21-day period.

Results: Rejuvenation Dependent on Bone Marrow Interaction

The researchers observed that young serum alone had no effect on skin aging markers in either static or dynamic skin-only cultures. However, when skin tissue was co-cultured with bone marrow-derived cells, significant changes occurred.

Skin in the combined system treated with young serum showed increased cell proliferation, indicating improved regenerative potential, and a reduction in biological age as measured by DNA methylation clocks. Bone marrow cells also exhibited improved mitochondrial function and changes in cell composition, particularly an increase in early progenitor cells.

These findings suggest that bone marrow-derived cells respond to young serum by producing signaling proteins that influence skin behavior. Without these intermediary cells, the rejuvenating effects were not observed.

Further proteomic analysis identified 55 proteins that were differentially expressed in bone marrow cells exposed to young versus old serum. Of these, seven proteins were tested individually on aged skin cells. Several—including CHI3L1, CD55, and MMP-9—improved markers related to skin aging, such as collagen production, mitochondrial activity, and cellular plasticity.

The Impact: Identification of Key Rejuvenating Proteins

This discovery highlights specific proteins that may serve as future targets in skin regeneration research. While the results are promising, they were obtained in controlled lab conditions. These findings are not yet applicable to clinical treatments but offer a potential foundation for developing non-invasive skin therapies that mimic the effects of youthful blood composition.

Future Perspectives and Conclusion

The study underscores the importance of systemic and inter-organ communication in skin aging. By incorporating bone marrow-derived cells into the experimental model, the researchers created a more physiologically accurate system to study how circulating factors influence tissue aging.

Although the evidence supports the idea that bone marrow cells mediate the effects of young serum on skin, additional research is needed. Future studies using aged skin models, extended time frames, and clinical validation will be essential to explore therapeutic possibilities.

As an experimental approach, this research adds valuable knowledge to the biological mechanisms of skin aging and could inform future strategies in regenerative medicine and dermatology.

Click here to read the full research paper published in Aging (Aging-US).

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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DoliClock: A Lipid-Based Clock for Measuring Brain Aging

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“Aging is a multifaceted process influenced by intrinsic and extrinsic factors, with lipid alterations playing a critical role in brain aging and neurological disorders.”

A new study published recently as the cover of Aging Volume 17, Issue 6, describes a new method to estimate how fast the brain is aging. By analyzing lipids, or fat molecules, in brain tissue, researchers from the National University of Singapore and Hanze University of Applied Sciences created a biological “clock” called DoliClock. This innovation highlights how conditions such as autism, schizophrenia, and Down syndrome are associated with accelerated brain aging.

Understanding Brain Aging

As people grow older, their brains naturally change. However, in many neurological disorders, these changes seem to appear earlier and progress more rapidly. Disorders like autism, schizophrenia, and Down syndrome reduce quality of life and contribute to premature death. Scientists have long searched for better ways to measure biological age in the brain to understand these processes and develop strategies to slow them down.

Most existing methods for estimating biological age rely on genetic markers, such as DNA methylation, which are chemical modifications of DNA. While useful, these approaches may not fully capture the complexity of aging, especially in the brain. Lipids, which are essential components of brain cells and play important roles in energy storage and signaling, offer another perspective.

The Study: Building a Lipid-Based Aging Clock

A team led by first author Djakim Latumalea and corresponding author Brian K. Kennedy introduced DoliClock, a model that predicts brain age using lipid profiles from the prefrontal cortex. This region of the brain, located just behind the forehead, plays a key role in decision-making, memory, and emotional regulation.

The study titled “DoliClock: a lipid-based aging clock reveals accelerated aging in neurological disorders” analyzed post-mortem brain samples from individuals with and without neurological conditions such as autism, schizophrenia, and Down syndrome.

The researchers focused on a class of lipids called dolichols, which are involved in vital cellular processes such as protein transport and glycosylation. These lipids tend to accumulate in brain tissue as people age, making them promising markers for measuring biological aging.

Results: Lipids Reflect the Pace of Aging

The DoliClock model showed that dolichol levels in the brain increased gradually with age. This change became particularly noticeable around the age of 40, suggesting a shift in how the brain regulates lipid metabolism during midlife. In addition to dolichols, the researchers observed an increase in entropy, a measure of disorder in lipid composition, which also intensified around this age.

When applied to brain samples from individuals with neurological disorders, DoliClock revealed significant differences. Samples from people with autism, schizophrenia, and Down syndrome showed higher predicted biological ages compared to their actual ages. This finding indicates that these disorders are associated with accelerated brain aging. The results align with previous studies using other biological clocks but add a new layer of understanding by focusing on lipid metabolism.

The Impact: A New Window into Brain Aging

DoliClock represents an important step in aging research because it demonstrates how lipid profiles can serve as markers of biological age. Unlike genetic markers, which may not fully capture brain-specific changes, lipidomic data directly reflect the brain’s structure and metabolic state. Dolichols, in particular, emerged as strong indicators of aging and may also play a role in the development of neurological disorders. This lipid-based clock could help scientists better understand the brain aging process and identify individuals at risk of premature decline.

Future Perspectives and Conclusion

DoliClock opens new possibilities for studying the molecular basis of brain aging. Although the current study used post-mortem brain tissue, future research could adapt this approach for use with more accessible samples. Similar lipid signatures might eventually be detectable in blood or cerebrospinal fluid, offering a non-invasive way to monitor brain health. Such tools could support early diagnosis and help track the effectiveness of treatments designed to slow brain aging.

Investigating how interventions such as dietary changes or medications affect lipid-based aging markers could also lead to new strategies for promoting healthy brain aging, making DoliClock a promising foundation for further exploration in aging research and brain health.

Click here to read the full research paper published in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Oxygen Deprivation and the Aging Brain: A Hidden Trigger for Cognitive Decline

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“As advanced age is associated with increased incidence of hypoxia-associated conditions such as asthma, emphysema, ischemic heart disease, heart failure, and apnea, our findings have important implications for many people.”

As we age, our brains become more sensitive to stress and disease. A recent study sheds light on a lesser-known risk: reduced oxygen levels. The study, titled “Defining the hypoxic thresholds that trigger blood-brain barrier disruption: the effect of age” and recently published as the cover for Volume 17, Issue 5 of Aging (Aging-US), found that low oxygen—also called hypoxia—can harm the aging brain by disrupting the blood-brain barrier (BBB). This damage may contribute to cognitive decline, memory problems, and an increased risk of dementia.

Understanding Hypoxia in the Brain

The brain relies on a steady supply of oxygen to stay healthy. When oxygen levels fall—a condition known as hypoxia—the brain undergoes changes to adapt. These changes include the remodeling of blood vessels and, importantly, a weakening of the blood-brain barrier. The BBB acts as a filter, protecting brain tissue from harmful substances. When it breaks down, it can lead to inflammation, brain cell damage, and cognitive issues.

Hypoxia is common in older adults, especially those with conditions like sleep apnea, chronic obstructive pulmonary disease (COPD), heart failure, and asthma. That is why understanding the connection between low oxygen and the aging brain is crucial for preventing long-term neurological damage.

The Study: Exploring Brain Vulnerability to Hypoxia

To investigate how age affects the brain’s response to low oxygen, researchers at the San Diego Biomedical Research Institute studied young and old mice. They exposed the mice to different levels of oxygen—from normal (21%) down to 8%—to see at what point the BBB  begins to fail. The study by Arjun Sapkota, Sebok K. Halder, Richard Milner, also tracked how sensitivity to hypoxia changes across the lifespan, examining mice from 2 to 23 months old.

The Results: Low Oxygen Damages the Blood-Brain Barrier in Older Brains

The results showed that older mice experienced blood-brain barrier disruption at higher oxygen levels—around 15%—compared to younger mice, which only showed damage at more severe hypoxia (13%). The damage in aged mice was also more severe: their BBB was four to six times leakier than in young mice under the same conditions.

Interestingly, the increased brain vulnerability began earlier than expected. Mice showed greater sensitivity to hypoxia between the ages of 2 and 6 months and again between 12 and 15 months. Additionally, microglia—immune cells in the brain—were more reactive in older mice, even at mild oxygen reductions. This suggests that as we age, the brain becomes not only more sensitive to hypoxia but also more prone to inflammation.

The Breakthrough: Understanding the Link Between Hypoxia and Cognitive Decline

This study is the first to clearly define how the threshold for oxygen-related brain damage changes with age. In simple terms, oxygen levels that are safe for young individuals can harm older adults. This discovery helps explain why conditions like sleep apnea, which reduce oxygen during sleep, are linked to higher dementia risk in older populations.

The Impact: A New Approach to Brain Health in Aging Populations

For older adults, keeping oxygen levels within a healthy range could be essential to protecting brain function. The study also has practical implications for people traveling to high altitudes. Oxygen levels similar to 15%, which were enough to cause BBB damage in aged mice, are found at elevations around 8,600 feet.

These findings highlight the importance of monitoring oxygen exposure, especially for those with chronic illnesses. Strategies to strengthen the blood-brain barrier may help reduce the risk of hypoxia-induced cognitive decline in aging individuals.

Future Perspectives and Conclusion

The aging brain is more vulnerable to low oxygen than previously believed. Even mild reductions in oxygen can lead to blood-brain barrier disruption, brain inflammation, and cognitive problems. This study offers valuable insights that can help guide future treatments aimed at protecting the brain in older adults.

For anyone living with respiratory or heart conditions, this research delivers an important message. Preventing hypoxia is just as crucial as treating illness. Monitoring and managing oxygen levels may not only extend lifespan but also help ensure better brain health and quality of life as we age.

Click here to read the full research paper in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Fighting Premature Aging: How NAD+ Could Help Treat Werner Syndrome

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“Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER (WRN) gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure.”

Werner syndrome is a rare condition marked by accelerated aging. A recent study, featured as the cover paper in Aging (Aging-US), Volume 17, Issue 4, led by researchers at the University of Oslo and international collaborators, suggests that nicotinamide adenine dinucleotide (NAD+), a vital molecule involved in cellular energy production, may be key to understanding this disease and developing future strategies to manage it.

Understanding Werner Syndrome

Werner syndrome (WS) is a rare genetic condition that causes people to age more quickly than normal. By their 20s or 30s, individuals with WS often show signs typically associated with older age, such as cataracts, hair loss, thinning skin, and heart disease. This premature aging is caused by mutations in the WRN gene, which normally helps repair DNA and protect cells from damage. While the WRN gene’s role in maintaining genetic stability is well understood, the reasons behind the rapid decline of cells in WS patients are still not fully clear.

The Study: Investigating NAD+ in Werner Syndrome

Nicotinamide adenine dinucleotide levels naturally decline with age. In the study titled “Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation,” researchers investigated whether this decline is more severe in people with WS and whether restoring NAD+ levels could help slow the aging process in these patients.

The research team, led by first author Sofie Lautrup and corresponding author Evandro F. Fang, used human stem and skin cells from WS patients, as well as gene-edited cells that mimic WS by lacking the WRN gene. These were always compared to control cells isolated from healthy individuals.

The researchers tracked how WRN deficiency affected NAD+ levels in mitochondria, the parts of the cell that generate energy. They then tested whether boosting NAD+ using a compound called nicotinamide riboside (NR)—a form of vitamin B3—could help restore normal cellular function. The team also used other strategies to raise mitochondrial NAD+ directly, including overexpressing a transporter protein known as SLC25A51. Their goal was to determine whether these approaches could reverse aging-related damage and restore cell growth affected by WRN mutations.

The Results: NAD+ Can Reduce Aging Signs

The findings confirmed that WRN-deficient cells had lower levels of mitochondrial NAD+ and showed signs of cellular aging, such as increased senescence and reduced proliferation. Treating these cells with NR significantly reduced aging markers and restored some normal functions in both stem and skin cells from WS patients. In healthy control cells, NR had no such effect, suggesting it works specifically in the context of NAD+ deficiency.

However, increasing NAD+ either through NR supplementation or by enhancing mitochondrial transport was not enough to fully restore cell division in lab-grown cells lacking WRN. This result suggests that while NAD+ supplementation is beneficial, the WRN gene itself plays a unique and irreplaceable role in supporting healthy cell growth.

The Breakthrough: Linking Mitochondrial NAD+ to Cell Aging

This study reveals a deeper role for the WRN gene beyond DNA repair. It shows that WRN also helps regulate how NAD+ is produced and used within cells, particularly in mitochondria. Without WRN, this system becomes unbalanced, accelerating cell aging. While boosting NAD+ helped reduce aging features in WS cells, the findings make clear that NAD+ therapy alone cannot replace the broader functions of WRN.

The Impact: A Step Toward Slowing Down Cellular Aging

This is the first study to directly show how low mitochondrial NAD+ contributes to premature aging in WS. Beyond its relevance to WS, the research highlights the broader potential of targeting NAD+ metabolism as a strategy for addressing age-related diseases. By increasing our understanding of how energy production affects aging, this study opens the door to future treatments aimed at promoting healthier aging across a wider population.

Future Perspectives and Conclusion

This study offers promising new insights but also demonstrates the complexity of cellular aging. The WRN gene plays a much broader role than DNA repair alone. It appears to regulate networks of genes linked to metabolism and genome organization. While boosting NAD+ can reduce some signs of cellular damage, it cannot fully compensate for the loss of WRN function.

Looking ahead, further research will be crucial to understanding how NAD+ operates in different parts of the cell and how it might work in combination with other treatments. For individuals with Werner syndrome, and potentially for the wider aging population, these findings bring us closer to future therapies aimed at improving health and longevity. 

Click here to read the full research paper in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Senolytic Compounds Show Promise in Targeted Alzheimer’s Treatments

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“Cellular senescence is a hallmark of aging and the age-related condition, Alzheimer’s disease (AD).”

Could a class of drugs that clear aging cells also help treat Alzheimer’s disease? A recent study, featured as the cover for Aging (Volume 17, Issue 3), titled “Differential senolytic inhibition of normal versus Aβ-associated cholinesterases: implications in aging and Alzheimer’s disease,” suggests they might—and with remarkable precision.

Understanding Alzheimer’s Disease

Alzheimer’s disease is a progressive neurological disorder that gradually steals memory, independence, and a person’s sense of identity. A defining feature of Alzheimer’s is the buildup of amyloid-β (Aβ) plaques—sticky protein clumps that interfere with communication between brain cells. This disruption is closely linked to changes in a group of enzymes called cholinesterases, especially acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These enzymes normally play a vital role in regulating neurotransmitters critical for memory, learning, and cognitive function. In Alzheimer’s, however, their behavior changes significantly, particularly when they interact with Aβ plaques.

The Study: Exploring Senolytics for Alzheimer’s Enzyme Inhibition

A research team from Dalhousie University in Canada looked into whether senolytic compounds—a class of drugs that eliminate damaged, aging cells often referred to as “zombie” cells—could also target the harmful forms of cholinesterase enzymes found in Alzheimer’s disease. Their goal was to see if these compounds could selectively inhibit the disease-associated versions of AChE and BChE, without affecting the healthy forms that are essential for normal brain function.

Led by Dr. Sultan Darvesh, the study tested six compounds: five senolytics—dasatinib, nintedanib, fisetin, quercetin, and GW2580—and one nootropic, meclofenoxate hydrochloride, known for its memory-enhancing potential. The researchers used post-mortem brain tissue from Alzheimer’s patients, enzyme activity assays, and computer modeling to examine how these compounds interact with the enzymes.

The Challenge: Targeting the Right Enzymes

One of the limitations of current Alzheimer’s treatments is that they do not distinguish between the normal and the altered forms of cholinesterases. While these drugs can raise levels of the memory-related chemical acetylcholine and improve cognitive function, they often come with side effects due to their broad activity. A more precise approach—targeting only the versions of AChE and BChE tied to Aβ plaques—could offer better outcomes with fewer drawbacks.

The Results: Senolytics Show Precision in Enzyme Targeting

The results were promising. Some of the senolytics tested, like dasatinib and nintedanib, effectively blocked the cholinesterases attached to Aβ plaques without affecting the normal versions of these enzymes in healthy brain tissue. Meclofenoxate also showed strong activity against the disease-associated forms. Interestingly, this selectivity was linked to how these compounds bind to the enzymes. Instead of locking onto the main active site, many of them attached to alternative regions, known as allosteric sites, which are only altered in the plaque-associated forms. This type of binding allowed the compounds to distinguish between harmful and healthy enzymes.

The Breakthrough: Targeting the Disease, Preserving the Brain

This study is the first to show that certain senolytic and cognitive-enhancing drugs can selectively inhibit the dysfunctional versions of cholinesterases found in Alzheimer’s without affecting their normal forms. This level of precision could mark a major step forward in Alzheimer’s therapy.

The Impact: A Dual-Action Path to Treating Alzheimer’s

By focusing on only the problematic forms of AChE and BChE, this approach could lead to Alzheimer’s treatments that better preserve cognitive function while avoiding side effects. The research also bridges two important areas of study: aging and neurodegeneration. It suggests that drugs developed to slow aging might also be used as targeted treatments for Alzheimer’s, offering a two-in-one therapeutic advantage. 

Future Perspectives and Conclusion

Although more research is needed, especially in living models and clinical trials, the potential of the findings is encouraging. They lead the way for a new generation of Alzheimer’s treatments that are more targeted and safer.

By understanding better how aging and brain disease intersect at the cellular level, scientists may be moving closer to developing more effective and personalized approaches to combat Alzheimer’s.

Click here to read the full research paper in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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How Radiation Therapy Affects Tumors: Glioblastoma vs. Low-Grade Gliomas

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“These insights underscore the importance of personalized treatment approaches and the need for further research to improve radiotherapy outcomes in cancer patients.”

Radiation therapy or radiotherapy, is a common treatment for cancer, but its effectiveness differs across patients. A recent study published as the cover for Volume 17, Issue 2 of Aging explored why this happens. The findings provide valuable insights, particularly for brain cancers like glioblastoma (GBM) and low-grade gliomas (LGG).

Understanding Glioblastoma and Low-Grade Gliomas

Glioblastoma and LGG are both brain tumors, but they behave in very different ways. GBM is highly aggressive, with most patients surviving only 12 to 18 months, even with surgery, chemotherapy, and radiation therapy. LGG, on the other hand, grows more slowly, and many patients live for decades with proper care.

Despite their differences, LGG and GBM are biologically linked. Some LGG tumors eventually transform into GBM, making early treatment decisions critical. Given radiation therapy’s effectiveness in GBM, it has often been assumed that LGG patients would also benefit from it. However, a new study titled “Variability in radiotherapy outcomes across cancer types: a comparative study of glioblastoma multiforme and low-grade gliomas” challenges this assumption.

The Study: Investigating Radiation Therapy’s Impact on Cancer Patients Survival

A research team led by first author Alexander Veviorskiy from Insilico Medicine AI Limited, Abu Dhabi, UAE, and corresponding author Morten Scheibye-Knudsen from the Center for Healthy Aging, University of Copenhagen, studied how radiation therapy affects cancer patient survival. They examined data from The Cancer Genome Atlas (TCGA), which includes 32 types of cancer. When they found that GBM and LGG had very different survival outcomes after radiation, they decided to focus on these two types of brain cancer. To learn more about their differences, gene expression and molecular pathways connected to radiation therapy responses were studied.

The Challenge: Why Radiation Therapy Works Only in Certain Tumors

Radiation therapy is an important cancer treatment, but its success is not the same for everyone. Even patients with the same type of cancer can respond differently, making it difficult to predict who will benefit. Understanding why some tumors are sensitive to radiation while others resist it is key to improving treatment and patient survival.

The Results: Radiation Therapy Works for Glioblastoma but Not for Low-Grade Gliomas

Overall, GBM had the highest percentage of patients receiving radiation therapy (82%), followed by LGG (54%). When researchers compared survival outcomes, they found that while radiation improved survival in breast cancer and GBM patients, it had a negative effect on patients with lung adenocarcinoma and LGG. This led researchers to take a closer look at GBM and LGG, especially since LGG can develop into GBM over time.

A key discovery was how GBM and LGG regulate DNA repair differently. GBM tumors have weak DNA repair activity, making them more vulnerable to radiation-induced damage. LGG tumors, however, activate more DNA repair pathways, allowing cancer cells to survive radiation and potentially making treatment less effective.

The immune response to radiation therapy was also different. In GBM, radiation triggered an immune response, which may help fight the tumor. In LGG, however, immune activation was significantly lower, meaning that radiation therapy did not enhance the body’s ability to attack cancer cells. This fact may contribute to worse survival outcomes for LGG patients after treatment.

Further genetic analysis revealed that ATRX gene mutations made GBM and LGG patients more sensitive to radiation. On the other hand, higher EGFR gene activity was linked to lower survival rates after radiation in LGG patients. Similar findings for GBM tumors indicate treatment resistance.

The Breakthrough: Toward Personalized Treatment

This study offers new insights into why radiation therapy benefits certain brain tumors while being less effective, particularly in GBM and LGG. Finding important biological factors, like DNA repair activity, immune response, and genetic changes that may serve as biomarkers, will help radiation therapy be more precisely tailored to each patient’s unique tumor profile. 

The Impact: Rethinking Glioblastoma and Low-Grade Gliomas Treatment

These findings highlight the importance of precision medicine in brain cancer treatment. Instead of automatically recommending radiation therapy for all LGG patients, oncologists should consider genetic testing to determine whether this treatment will be beneficial or not. If not, alternative treatments may be necessary. Immunotherapy and targeted drugs against EGFR could provide better outcomes for patients who do not respond well to radiation therapy.

For GBM, researchers are investigating ways to enhance radiation’s effectiveness by combining it with DNA repair inhibitors, such as PARP inhibitors. These drugs could increase tumor sensitivity to radiation and improve survival rates. 

Conclusion

Advancing cancer treatment requires a personalized approach. Identifying biomarkers that predict how GBM and LGG tumors respond to radiation therapy can help clinicians make more informed treatment decisions, ensuring that patients receive the most effective and least harmful therapies. By uncovering key genetic and molecular insights, this study moves the field closer to individualized brain cancer treatments, improving survival rates while reducing unnecessary risks for patients.

Click here to read the full research paper in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Exploring Baseline Variations and Mechanical Loading-Induced Bone Formation in Young-Adult and Aging Mice through Proteomics

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Bone mass declines with age, and the anabolic effects of skeletal loading decrease. While much research has focused on gene transcription, how bone ages and loses its mechanoresponsiveness at the protein level remains unclear.

Researchers Christopher J. Chermside-Scabbo, John T. Shuster, Petra Erdmann-Gilmore, Eric Tycksen, Qiang Zhang, R. Reid Townsend, Matthew J. Silva from Washington University School of Medicine and Washington University in St. Louis, MO, share their findings which underscore the need for complementary protein-level assays in skeletal biology research.

On October 12, 2024, their research paper was published as the cover of Aging (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science), Volume 16, Issue 19, entitled, “A proteomics approach to study mouse long bones: examining baseline differences and mechanical loading-induced bone formation in young-adult and old mice.”

THE STUDY

In this study, the tibias of young-adult and old mice were analyzed using proteomics and RNA-seq techniques, while the femurs were examined for age-related changes in bone structure. A total of 1,903 proteins and 16,273 genes were detected through these analyses. Multidimensional scaling demonstrated a clear separation between the young-adult and old samples at both the protein and RNA levels. Furthermore, 93% of the detected proteins were also identifiable by RNA-seq, and the abundance of these shared targets showed a moderately positive correlation. Additionally, differential expression analysis revealed 183 age-related differentially expressed proteins and 2,290 differentially expressed genes between young-adult and old bone samples.

Proteomic and RNA-seq analyses were conducted on paired tibias from young-adult and old mice to study age-related differences and the effects of mechanical loading on bone formation. The results showed distinct differences in protein and gene expression between the two age groups. Many of the significantly upregulated and downregulated proteins and genes in old bone have been associated with bone phenotypes in genome-wide association studies (GWAS). The study also identified age-related differentially expressed proteins and genes involved in bone phenotypes and aging processes. Integrated analysis with GWAS data revealed eight targets that may be relevant to human disease, including Asrgl1 and Timp2. Furthermore, co-expression analysis identified an age-related module indicating baseline differences in TGF-beta and Wnt signaling. Baseline age-related differences in ECM/MMPs and TGF-beta signaling were detected in both the proteome and transcriptome. Following mechanical loading, the proteome showed distinct pathway, protein class, and process enrichments, with temporal differences observed between young-adult and old mice.

Overall, the findings provide valuable insights into the molecular mechanisms underlying age-related changes and the response to mechanical loading in mouse long bones.

DISCUSSION

This study aimed to compare the proteome and transcriptome of tibias from young-adult and old mice under baseline conditions and analyze changes in the bone proteome in response to mechanical loading. The researchers successfully developed a proteomics method to detect protein-level changes in cortical bone and used it to perform proteomic and RNA-seq analyses on tibias from both young-adult and old mice. They observed a moderately positive correlation between the proteome and transcriptome in bone tissue. Age-related differences were detected at both the protein and RNA levels, with altered TGF-beta signaling and changes in extracellular matrix (ECM) and matrix metalloproteinases (MMPs) protein and transcript levels in old bones. The researchers identified Tgfb2 as the most reduced Tgfb transcript in old bone, predominantly expressed by osteocytes. Proteomic analysis of the loading response showed modest changes compared to age-related differences, with fewer protein-level changes in old bones. The findings suggest that proteomics is a valuable tool for studying bone biology and can provide insights into protein-specific changes in aging.

The data obtained from the analysis were subjected to various statistical and data exploration techniques. Differential expression analysis was performed to compare protein abundance between different groups. Total RNA was extracted from the bones using TRIzol, and its integrity and concentration were measured. The bones were also processed for paraffin sectioning and RNA in situ hybridization.

Overall, the study involved the collection and analysis of bone samples from female mice to investigate age-related changes and loading responses in the skeletal system.

Click here to read the full research paper in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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How Single Housing Impacts Growth and Lifespan in African Turquoise Killifish

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“[…] our results suggest that sharing housing with others in early life might influence whole-life attributes, potentially leading to specific life history traits beyond the typical relationship between the growth rate and lifespan.”

In this research, Chika Takahashi, Emiko Okabe, Masanori Nono, Saya Kishimoto, Hideaki Matsui, Tohru Ishitani, Takuya Yamamoto, Masaharu Uno, and Eisuke Nishida from the RIKEN Center for Biosystems Dynamics Research (BDR) in Hyogo, Japan; Brain Research Institute, Niigata University in Niigata, Japan; Research Institute for Microbial Diseases at Osaka University in Osaka, Japan; Kyoto University in Kyoto, Japan; and RIKEN Center for Advanced Intelligence Project (AIP), explored the effects of housing density during the juvenile stage on whole-life traits, including growth, fecundity, and lifespan, in African turquoise killifish. Their research paper was published on the cover of Aging (listed by MEDLINE/PubMed as Aging (Albany NY) and as Aging-US by Web of Science), Volume 16, Issue 18, entitled, “Single housing of juveniles accelerates early-stage growth but extends adult lifespan in African turquoise killifish.”

THE STUDY

A study on African turquoise killifish examined the impact of housing density on juvenile growth. Newly hatched fish were kept in different densities ranging from 1 to 40 fish per tank. It was found that lower housing densities resulted in faster growth, with fish in single housing growing significantly larger than those in group housing. Additionally, single-housed fish reached sexual maturity earlier compared to group-housed fish at higher densities. Comparisons between group-housed and single-housed fish showed that housing conditions in the juvenile stage did not affect the appearance changes during sexual maturation. 

As the fish progressed to middle-aged adults, the rate of increase in body length slowed down, while body weight continued to increase. Differences in body weight between group-housed and single-housed fish persisted into old age, suggesting potential differences in body composition. Surprisingly, single-housed fish had a longer mean adult lifespan compared to group-housed fish, contradicting the commonly held belief that faster growth leads to shorter lifespan. Lower housing densities during the juvenile stage were also found to extend adult lifespan, further challenging the inverse correlation between growth rate and lifespan. These findings suggest that lower housing densities promote accelerated growth in the juvenile stage of African turquoise killifish.

The study also found that single-housed fish had a longer adult lifespan compared to group-housed fish. This led to the suspicion that the egg-laying period of single-housed fish might also be longer. To investigate this, the researchers conducted weekly monitoring of the number of eggs laid until the old adult stage. In group-housed fish, the number of eggs laid was high for the first two weeks, followed by a medium level for the subsequent five weeks, and then decreased. In contrast, single-housed fish showed a medium level of egg-laying for the first nine weeks, followed by a decrease. The cumulative number of live embryos was found to be lower in single-housed fish compared to group-housed fish. These findings suggest that while the number of eggs laid is not very high, single-housed fish have a longer egg-laying period than group-housed fish.

To investigate the potential reasons behind the reduction in offspring number and longer egg-laying period in single-housed fish, the researchers conducted RNA sequencing analysis of testes or ovaries at four life stages. These stages included the onset of sexual maturity, young adult, mature adult, and middle-aged adult. Interestingly, the analysis revealed that single-housed fish showed higher similarity to group-housed fish at earlier life stages compared to group-housed fish at the same life stage. For instance, in the testes, single-housed fish at stage II exhibited the highest similarity to group-housed fish at stage I. Similarly, in the ovaries, single-housed fish at stage II and III showed higher similarity to group-housed fish at stage I. These findings suggest that the rate of gonadal transcriptional change with life stage progression is slower in single-housed fish compared to group-housed fish.

The researchers identified differentially expressed genes (DEGs) between stage I and stage IV in group- and single-housed fish. In the testes, ribosome-related genes and cilium-related genes were highly enriched in DEGs with higher expression in stage I compared to stage IV, suggesting a link between life stage progression, testes development, and spermatogenesis. In the ovaries, growth-related genes and translation-related genes were highly enriched in DEGs with higher expression in stage I compared to stage IV, indicating a link between life stage progression, ovarian development, oogenesis, and aging. Comparing group-housed and single-housed fish at different stages, there were differences in the PC1 values, suggesting that single-housed fish exhibited slower progression of gametogenesis and gonadal maturation relative to life stage progression compared to group-housed fish.

To further investigate this, the researchers focused on specific genes related to spermatogenic differentiation, oocyte development, oocyte construction, and female gonad development. The expression of these genes showed slower changes with life stage progression in single-housed fish compared to group-housed fish in both the testes and ovaries. This suggests that single-housed fish may have slower rates of gametogenesis and gonadal maturation, leading to a lower proportion of mature sperm and oocytes in their gonads. Overall, the results indicate that, at the transcriptional level, the progression of gonadal maturation and ovarian aging is slower in single-housed fish compared to group-housed fish. This slower progression may explain the medium fecundity and extended egg-laying period observed in single-housed fish.

The liver was chosen for analysis as it plays a central role in organismal metabolic processes. Gene expression profiles of the livers were compared between group- and single-housed fish at two different ages: 7 weeks post-hatching (wph) and 14 wph. Surprisingly, despite the 2-week age difference, the correlation coefficients showed that group- and single-housed fish at 14 wph were highly similar. The researchers identified 1588 age-related differentially expressed genes (DEGs) between the two age groups. Hierarchical clustering based on the expression changes of these age-related genes demonstrated that the expression profiles of group- and single-housed fish were similar at 14 wph.

IN CONCLUSION

In summary, juvenile single housing in African turquoise killifish promotes faster growth, longer egg-laying periods, and extended lifespans compared to group housing. These findings challenge traditional assumptions about the relationship between growth and lifespan and shed light on the impact of early-life environmental conditions on overall life history.

Overall, the experiments involved maintaining and rearing the fish, measuring their body length and weight, analyzing RNA sequencing data, measuring lifespan, and counting the number of eggs laid. Statistical analysis was conducted to assess significant differences between groups.

Click here to read the full research paper in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

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