The most common human amyloid is aortic medial amyloid (AMA), caused by aggregation of a 50-amino acid peptide called medin, which is cleaved by an unknown mechanism from its parent protein, milk fat globulin EGF-factor 8 (MFGE8). Medin is present in the vessel wall of 97% of Caucasians aged over 50- years, yet despite its prevalence in the ageing population there is a very limited understanding of the mechanisms driving AMA. Despite several forms of amyloidosis, including AMA and Alzheimer's disease (AD), being frequently associated with ageing, there has been limited research to date on the effect of cellular 'ageing', termed senescence, on amyloidosis.

Senescent cells accumulate in the vasculature with age and undergo a range of phenotypic changes, including extracellular matrix (ECM) remodelling and increased secretion of inflammatory mediators. Researchers have confirmed a strong correlation between age and medin in the ECM of the medial layer of human aortic tissue. In vitro studies, using human vascular smooth muscle cells (VSMCs), demonstrated that the ECM synthesised by senescent cells contained medin in a fibril-like form. This was in contrast to the small, round aggregates found in the ECM from healthy, proliferative VSMCs, suggesting senescent cells create an environment permissive for medin aggregation. Further mechanistic studies found that small extracellular vesicles (sEVs) secreted from VSMCs carried medin as a cargo and were responsible for medin release and also its aggregation in the ECM. Importantly, senescent VSMCs showed enhanced sEV secretion and senescent sEVs could accelerate medin aggregation compared with sEVs from proliferative VSMCs.

The pathological effects of medin accumulation in the vasculature, as well as the forms of medin responsible for inducing damage, remain poorly understood. Studies have shown that small medin aggregates can induce endothelial cell dysfunction and inflammation while accumulation of fibrillar amyloid species can contribute to weakening and stiffening of the vessel wall. These effects may be particularly relevant to the cerebrovasculature as a recent study has shown that medin accumulates in the cerebral vessels with age and may enhance Aβ formation, leading to vascular stiffening in the brain and increased CAA burden. These data suggest that medin may represent a new therapeutic target for AD and CAA, to maintain a functioning and healthy cerebral environment during ageing.

Certain stem cells have a unique ability to move between growth compartments in hair follicles, but get stuck as people age and so lose their ability to mature and maintain hair color. A new study focused on cells in the skin of mice and also found in humans called melanocyte stem cells, or McSCs. Hair color is controlled by whether nonfunctional but continually multiplying pools of McSCs within hair follicles get the signal to become mature cells that make the protein pigments responsible for color.

This means that during normal hair growth, such cells continually move back and forth on the maturity axis as they transit between compartments of the developing hair follicle. It is inside these compartments where McSCs are exposed to different levels of maturity-influencing protein signals. Specifically, the research team found that McSCs transform between their most primitive stem cell state and the next stage of their maturation, the transit-amplifying state, and depending on their location. The researchers found that as hair ages, sheds, and then repeatedly grows back, increasing numbers of McSCs get stuck in the stem cell compartment called the hair follicle bulge. There, they remain, do not mature into the transit-amplifying state, and do not travel back to their original location in the germ compartment, where WNT proteins would have prodded them to regenerate into pigment cells.

For unknown reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations, which leads to hair greying in most humans and mice. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems.

Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.

Population ageing leads to increased demand for health and social care and associated cost pressures. By 2028, 25% of England's population will be aged 65 and over, with 8% classified as frail. Frailty increases with age and is associated with higher healthcare utilization, and its determinants are key for effective healthcare services provision. Studies have identified protective (e.g. higher wealth, increased social support) and harmful (e.g. lower wealth, educational achievement, presence of long-term conditions, being female) factors associated with frailty progression. However, there is a lack of evidence on the impact of multiple long-term conditions (LTCs) longitudinally as a separate determinant of frailty progression. LTCs are defined as "A long term condition is one that cannot currently be cured but can be controlled with the use of medication and/or other therapies."

This study aimed to explore longitudinally the impact of multiple LTCs on frailty progression separately for males and females due to behavioural, social, and biological differences. A functional frailty measure (FFM) was used to examine putative determinants of frailty progression among participants aged 65 to 90 in the English Longitudinal Study of Ageing (ELSA), across nine waves (18 years) of data collection. A multilevel growth model was fitted to measure the FFM progression over 18 years, grouped by LTC categories (zero, one, two and more).

There were 2,396 male participants at wave 1, of whom 742 (31.0%) had 1 LTC and 1147 (47.9%) had ≥2 LTCs. There were 2,965 females at wave 1 of whom 881 (29.7%) had one LTC and 1,584 (53.4%) had ≥2 LTCs. The FFM increased 4% each 10 years for the male participants with no LTCs, while it increased 6% per decade in females. The FFM increased with the number of LTCs, for males and females. The acceleration of FMM increases for males with one long-term health condition or more; however in females the acceleration of FMM increases when they have two LTCs or more. In conclusion, frailty progression accelerates in males with one LTCs and females with two LTCs or more. Health providers should be aware of planning a suitable intervention once the elderly have two or more health conditions.

There is converging evidence that young blood conveys cells, vesicles, and molecules able to revitalize function and restore organ integrity in old individuals. Here, we assessed the effects of young rat plasma on the lifespan, epigenetic age, and healthspan of old female rats. Beginning at 25.3 months of age, a group of 9 rats (group T) was intraperitoneally injected with plasma from young rats (2 months) until their natural death. A group of control rats of the same age, received no treatment. Blood samples were collected every other week.

Survival curves showed that from age 26 to 30 months, none of the T animals died, whereas the survival curve of C rats began to decline at age 26 months. The external appearance of the T rats was healthier than that of the C counterparts. Blood DNA methylation (DNAm) age versus chronological age showed that DNAm age in young animals increased faster than chronological age then slowed down progressively, entering a plateau after 27 months. Immediately after the start of the treatment, the DNAm age (i.e., epigenetic age) of the treated rats fell below the DNAm age of controls and remained consistently lower until the end of their lives.

Assessment of each experimental group showed that the blood DNA methylation levels of 1638 CpGs were different between treated and control blood samples. Of these, 1007 CpGs exhibited increased methylation, with age while 631 CpGs showed decreased methylation levels. When rats were grouped according to the similarities in their differential blood DNA methylation profile, samples from the treated and control rats clustered in separate groups. Analysis of promoter differential methylation in genes involved in systemic regulatory activities has revealed specific gene ontology (GO) term enrichment related to the insulin-like factors (IGFs) pathways as well as to cytokines and chemokines associated with immune and homeostatic functions. We conclude that young plasma therapy may constitute a natural noninvasive intervention for epigenetic rejuvenation and health enhancement, readily translatable to the clinic.

James Peyer, the CEO of the New York-based biotech company Cambrian Bio - which seeks to develop therapeutics to lengthen healthspan - says the first geroprotective drug to gain FDA approval may be something that is already known today - perhaps a drug already approved for another indication - and has only to be validated through clinical trials for longevity. "We have actually 80 interventions, of which about 20 are drugs that extend healthy lifespan in mice," he says, referring to all the known drugs on the market that could potentially be repurposed as well as all the experimental compounds in the pipeline not yet approved to treat any disease that look promising as future geroprotective drugs. Probably a handful of the 80 have sufficient evidence to support running a large clinical trial. But therein lies the problem.

Doing clinical trials for longevity is hard. It's expensive. Historically, many have even said it's impossible. "If you took an experimental drug, and I took a placebo, how long would we have to wait to see a real outcome?" Peyer asks me. "Six years. They take six years and they cost 150 million. If you're going to take a drug that has never demonstrated human safety and efficacy before and try to go straight into that six year, 150 million shot on goal, and then maybe afterwards you'll have revenues. It's risky." Six costly years, six risky years - and there's no way around it. That's why people always warned him it couldn't be done.

Instead a preventive medicine is typically tested first for its ability to treat a specific illness. Once it proves safe in humans and effective for that smaller indication, then it moves into the more costly, larger prevention trials. And that's how many companies in the field are moving forward-using what Peyer calls the stepping-stone approach. The idea of targeting treatments for specific age-related diseases is to create value. It avoids the six-year risk of a broader longevity trial and instead tests the drug in well-defined populations, perhaps even people who have a genetic disease and will be highly likely to benefit from the therapy. They may respond more quickly, show results sooner, and allow for shorter, less expensive clinical trials.

The basic idea is simple, says Joe Betts-LaCroix, CEO of the San Francisco-based biotech company Retro Biosciences. "You can start with a disease that has the most acute manifestation in the shortest amount of time with response to some step change in an aging mechanism, produce that as a therapy that gets approved by a health authority, and then slowly expand from there. The idea is that if you can intervene really well in one aging pathway, you can then treat and or prevent multiple downstream diseases at the same time with one therapy."

Circular DNA, known as extrachromosomal DNA or ecDNA, often harbor cancer-associated genes called oncogenes. Because they can exist in large numbers in a cell, they deliver a super-charged growth signal that can override a cell's natural programming. They also contain genes likely to dampen the immune system's response to a nascent cancer, the researchers found. Previous research had suggested that the circles, which are widespread in human cancers but rarely found in healthy cells, primarily arise in advanced tumors as the abnormal cells increasingly botch the intricate steps required to copy their DNA before each cell division. But the new study shows that the circles can be found even in precancerous cells - and their presence jump-starts a cancerous transformation. Blocking their formation, or their effect on the cells that carry them, might stop cancers from developing, the researchers believe.

The researchers assessed the prevalence of ecDNA, and identified the genes they carried, in biopsies from nearly 300 people with Barrett's esophagus or esophageal cancer, where individual patients were studied as the cancer developed. They found that the prevalence of ecDNA increased from 24% to 43% in early- versus late-stage esophageal cancer, indicating the continual formation of the DNA circles during cancer progression. More tellingly, they found that 33% of people with Barrett's esophagus who developed esophageal cancer had ecDNA in their precancerous cells. In contrast, only one out of 40 people who didn't develop cancer had cells with ecDNA, and that individual passed away due to another cause.

Immunosenescence is a complex process characterized by an age-related remodelling of the immune system. The prominent effects of the immunosenescence process is the thymic involution and, consequently, the decreased numbers and functions of T cells. Since thymic involution results in a collapse of the T-cell receptor (TCR) repertoire, a reliable biomarker of its activity is represented by the quantification of signal joint T-cell receptor rearrangement excision circles (sjTRECs) levels. Although it is reasonable to think that thymic function could play a crucial role on elderly survival, only a few studies investigated the relationship between an accurate measurement of human thymic function and survival at old ages.

By quantifying the amount sjTRECs by real-time polymerase chain reaction (PCR), the decrease in thymic output in 241 nursing home residents was evaluated to investigate the relationship between thymic function and survival at old ages. The mean age of these patients was 78.4 years. We found that low sjTREC levels were associated with a significant increased risk of mortality at older ages. Nursing home residents with lower sjTREC exhibit a near 2-fold increase in mortality risk compared to those with sjTREC levels in a normal range.

In conclusion, thymic function failure is an independent predictor of mortality among elderly nursing home residents. sjTREC represents a biomarker of effective ageing as its blood levels could anticipate individuals at high risk of negative health outcomes. The identification of these subjects is crucial to manage older people's immune function and resilience, such as, for instance, to plan more efficient vaccine campaigns in older populations.

Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness, remain unclear. Here, we sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow (BM). We identify Netrin-1 as a critical regulator of BM niche cell aging. Niche-specific deletion of Netrin-1 induces premature aging phenotypes within the BM microenvironment, while supplementation of aged mice with Netrin-1 rejuvenates aged niche cells and restores competitive fitness of aged blood stem cells to youthful levels.

We show that Netrin-1 plays an essential role in maintaining active DNA damage responses (DDR), and that aging-associated decline in niche-derived Netrin-1 results in DNA damage accumulation within the BM microenvironment. We show that Netrin-1 supplementation is sufficient to resolve DNA damage and restore regenerative potential of the aged BM niche and blood stem cells to endure serial chemotherapy regimens.

Despite the growing interest by researchers into cellular senescence, a hallmark of aging, its role in human skin remains equivocal. The skin is the largest and most accessible human organ, reacting to the external and internal environment. Hence, it is an organ of choice to investigate cellular senescence and to target root-cause aging processes using senolytic and senomorphic agents. This review presents different aspects of skin cellular senescence, from physiology to pathology and signaling pathways. Premature cellular senescence can underlie pathological skin conditions. However, its role is ambiguous, and it seems that a distinction needs to be made between acute and chronic senescence. It appears that the chronic accumulation of senescent cells can have a detrimental effect on skin function, health, and aging, while acute stimulation of transient senescent cells plays an important role in wound healing.

In contrast to acute wound healing, chronic, nonhealing ulcers (e.g., murine model of diabetes, venous ulcers, radiation ulcers) are characterized by higher levels of senescence. Clearance of senescent cells with senolytics (i.e., dasatinib plus quercetin) has been shown to mitigate radiation ulcers. Additionally, it is well known that the regenerative capacity of the skin declines with age in conjunction with increased accumulation of senescent cells. Delayed wound healing was reported in young 8-week-old mice after the subcutaneous transfer of irradiated fibroblasts. In this case, the kinetics of wound healing were similar to those observed in naturally aging 2-year-old mice.

On the other hand, researchers have reported different senescent responses in younger (30.2 ± 1.3 years) vs. older (75.6 ± 1.8 years) healthy subjects in punch biopsy wounds. The second biopsy, taken for analysis, was performed several days after the first one. Induction of p21 and p53 was observed during healing in younger but not older skin. Therefore, transient appearance of senescent cells may be needed for proper healing of acute wounds, but their chronic presence delays healing. Moreover, senescent fibroblasts have also been found in keloid scars - lesions that result from abnormal wound healing and can be classified as benign skin tumors. It is believed that the appearance of aging is a desirable phenomenon in keloids as a mechanism potentially responsible for stopping the proliferation of fibroblasts and the progression of lesions.

Hair disorders can also be affected by senescent pathways. In an experimental model of age-related hair loss, hair follicle dermal stem cells exhibited features of senescent cells (overexpression of p16INK4a and SA-β-Gal). Additionally, increased senescence-associated secretory phenotype (SASP) components were detected in the mesenchymal niche of the hair follicle. Moreover, clearing senescent cells by a possible senolytic, FOXO4-DRI, reduced hair loss in progeroid aging mice. Additionally, hair follicle dermal papillary cells from the male balding scalp showed the loss of proliferative capacity. This phenomenon was associated with increased SA-β-Gal and p16INK4a/pRb expression. Moreover, knocking out p16INK4a promoted faster growth of hair follicle dermal papillary cells.

It is well-established that women experience disproportionately lower bone mass than men throughout their lives. Loss of bone mass accelerates with menopause, increasing the risk of osteoporosis and associated fractures for women as they age. To figure out why this happens, researchers looked at the differences in the ways bone is regulated in male and female mice, which share many similarities with humans and are important models for studying health and disease. They focused on specialized cells called osteoclasts, which help maintain bone health by breaking down and recycling old bone.

The researchers found reducing KDM5C disrupted cellular energy production in osteoclasts, which slowed down extracellular matrix resorption and preserved bone mass. Importantly, KDM5C is linked to X chromosomes, which means it is more active in females than in males. "Lowering KDM5C levels is like flipping a switch to stop an overactive extracellular matrix resorption process. The result is more bone mass, which ultimately means stronger bones. We're very excited about this work and look forward to carrying out future studies to refine our findings. At the end of the day, we hope these insights make a difference for people with osteoporosis."

The researchers worked from an old hypothesis that electric stimulation of damaged skin can be used to heal wounds. The idea is that skin cells are electrotactic, which means that they directionally 'migrate' in electric fields. This means that if an electric field is placed in a petri dish with skin cells, the cells stop moving randomly and start moving in the same direction. The researchers investigated how this principle can be used to electrically guide the cells in order to make wounds heal faster. Using a tiny engineered chip, the researchers were able to compare wound healing in artificial skin, stimulating one wound with electricity and letting one heal without electricity. The differences were striking.

"We were able to show that the old hypothesis about electric stimulation can be used to make wounds heal significantly faster. In order to study exactly how this works for wounds, we developed a kind of biochip on which we cultured skin cells, which we then made tiny wounds in. Then we stimulated one wound with an electric field, which clearly led to it healing three times as fast as the wound that healed without electric stimulation."

In the study, the researchers also focused on wound healing in connection with diabetes, a growing health problem worldwide. "We've looked at diabetes models of wounds and investigated whether our method could be effective even in those cases. We saw that when we mimic diabetes in the cells, the wounds on the chip heal very slowly. However, with electric stimulation we can increase the speed of healing so that the diabetes-affected cells almost correspond to healthy skin cells."

While the relationship between exercise and life span is well-documented, little is known about the effects of specific exercise protocols on modern measures of biological age. Transcriptomic age (TA) predictors provide an opportunity to test the effects of high-intensity interval training (HIIT) on biological age utilizing whole-genome expression data.

A single-site, single-blinded, randomized controlled clinical trial design was utilized. Thirty sedentary participants (aged 40-65) were assigned to either a HIIT group or a no-exercise control group. After collecting baseline measures, HIIT participants performed three 10 × 1 HIIT sessions per week for 4 weeks. Each session lasted 23 min, and total exercise duration was 276 min over the course of the 1-month exercise protocol. TA, 10-item perceived stress scale (PSS-10) score, Pittsburgh sleep quality index (PSQI) score, patient health questionnaire 9-item depression module (PHQ-9) score, and various measures of body composition were all measured at baseline and again following the conclusion of exercise/control protocols.

Transcriptomic age reduction of 3.59 years was observed in the exercise group while a 3.29-years increase was observed in the control group. Also, PHQ-9, PSQI, BMI, body fat mass, and visceral fat measures were all improved in the exercise group. A hypothesis-generation gene expression analysis suggested exercise may modify autophagy, mTOR, AMPK, PI3K, neurotrophin signaling, insulin signaling, and other age-related pathways. A low dose of HIIT can reduce an mRNA-based measure of biological age in sedentary adults between the ages of 40 and 65 years old. Other changes in gene expression were relatively modest, which may indicate a focal effect of exercise on age-related biological processes.

Telomerase preserves genomic integrity by maintaining and protecting the telomeres. Seminal findings from 1985 revealed the canonical role of telomerase and motivated investigations into potential therapeutic strategies to combat one of the hallmarks of ageing - telomere attrition. Since then, the field of telomere biology has rapidly expanded, with telomerase serving essential roles in cancer and cell development through its canonical function.

However, telomerase also exerts critical extra-telomeric functions through its protein (telomerase reverse transcriptase, TERT) and RNA components (telomerase RNA component, TERC). Telomerase re-activation or ectopic expression promotes survival and permits unlimited proliferation in tumours and healthy non-malignant cells. TERT gene therapies improve health and lifespan in ageing mice and mouse models of age-related diseases. The extra-telomeric functions of telomerase are critical to ageing. These include protection against oxidative stress, orchestration of chromatin modifications and transcription, and regulation of angiogenesis and metabolism (e.g. mitochondrial function and glucose control).

Given that these biological functions are key adaptations to endurance training and the recent meta-analytical findings that indicate exercise up-regulates TERT and telomerase, a comprehensive discussion on the implications of the canonical and extra-telomeric roles of telomerase is warranted. This review highlights the therapeutic benefits of telomerase-based treatments for idiopathic and chronic diseases that are linked to ageing. Discussion on the canonical and extra-telomeric roles of telomerase are presented, followed by a detailed summary of the evidence on how exercise influences telomerase. Finally, the potential cell signalling underpinning the exercise-induced modulation of telomerase are discussed with directions for future research.

Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions.

At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice.

Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.

It can be hypothesized that functional regeneration of osteochondral defects may occur through the activation of appropriate progenitor cells recruited from the surrounding tissues, such as the synovial membrane, upon the onset of the pro-regenerative phase from the local immune cells. Once these progenitors are activated by trauma, they migrate to the defect site where they attach, proliferate, and undergo chondrogenic differentiation to contribute to tissue regeneration. Subsequently, it can be hypothesized that elements in the synovial environment of osteoarthritis (OA) may interfere with any of these crucial steps, impairing the regenerative potential. These elements would then be a cause, and as a result, a target to treat and potentially cure OA in a clinically effective way.

The synovial fluid (SF) from OA patients was herein identified to be a major inhibitor of the regenerative process in an OA environment. Specifically, the heterogeneous cell population isolated from the SF showed a clear ability to migrate, attach, proliferate, and undergo chondrogenic differentiation, all steps crucial for functional regeneration to occur, under standard assay conditions. However, the presence of autologous SF (aSF) during any of these events drastically impaired these processes. Characterization of the SF cytokine composition linked these results to a specific pro-inflammatory profile, suggesting an imbalance between pro- and anti-inflammatory immune cells in the SF.

On the basis of these findings, an immunomodulatory cell treatment was developed with the goal of restoring joint homeostasis by mimicking crucial events seen during tissue regeneration. The treatment was based on anti-inflammatory cartilage-activated T cells (CATs), which upon coculture with adipose-derived mesenchymal stromal cells (aMSCs), induced chondrogenic priming of the progenitor cells. Intra-articular injection of the final coculture steered articular cartilage regeneration and restored joint homeostasis in a rat OA model. A later clinical evaluation in human patients showed improved quality of life, reduced pain, and articular cartilage regeneration in a compassionate use study.