Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research.

This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing". The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases.

The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.

Klotho (KL) is a longevity factor that declines in aging. Elevating KL boosts cognitive functions in mice through transgenic overexpression and acute peripheral administration. KL (secreted α-klotho) circulates as a hormone following cleavage from its transmembrane form and impacts insulin and fibroblastic growth factor (FGF) signaling, Wnt and N-methyl-d-aspartate receptor (NMDAR) functions. Systemic elevation of KL in mice increases synaptic plasticity, cognition, and neural resilience to aging, Alzheimer's, and Parkinson's disease-related toxicities. Notably, systemic administration of KL does not cross the blood-brain barrier. Human relevance for KL in brain health is supported by studies showing that individuals with elevated KL, due to genetic Klotho variation or other reasons, demonstrate better cognition, attenuated neuropathological measures, or decreased dementia risk in aging and Alzheimer's disease.

We sought to test whether a low-dose, subcutaneous administration of KL could, in parallel to mice, boost cognition in aged rhesus macaques, a type of non-human primate (NHP). Like humans, rhesus macaques undergo age-induced cognitive decline with synaptic changes, without significant neuronal loss, impairing brain regions, including the hippocampus and prefrontal cortex (PFC). Targeted earlier by aging, the PFC subserves executive functions such as working memory and, in rhesus macaques, shows age-induced deficits in neuronal firing, regulated protein kinase C (PKC) activity, neurotransmitter balance and structural decline.

Our primary goal was to test whether a KL dose in rhesus macaques that increases serum levels to a range present during the human lifespan, and is comparable to therapeutically effective increases in mice, can enhance cognition. Our secondary goal was to explore higher KL doses in rhesus macaques to test whether KL-mediated benefits on cognition could be dose-dependent. Our data show that KL (10 μg/kg) enhanced cognition in aging rhesus macaques, an effect that persisted for at least 2 weeks in measures of memory. KL-mediated cognitive enhancement similarly persisted in mice for at least 2 weeks, suggesting organizational, longer-lasting and beneficial effects on the synapse and brain. In both species, the cognitive effect outlasted the putative half-life of the hormone, 7 minutes in rodents and estimated at 29.5 hours in aging rhesus macaques.

Higher doses of KL (20 and 30 μg/kg) did not enhance cognition in monkeys. Of note, the higher doses tested did not impair cognition as the 2-5% changes were not significantly increased or decreased statistically; however, it remains to be determined whether doses even higher than those tested could impair cognition. Together, these data indicate that KL-mediated cognitive enhancement extends to NHPs in a complex genetic, anatomical, and functional brain similar to humans. These data also suggest that lower, more 'physiological' levels of the hormone in the body may be required for a therapeutic window of cognitive enhancement in humans.

Senescent cells that accumulate with age have been shown to contribute to age-related diseases and organ dysfunction and have attracted attention as a target for anti-aging therapy. In particular, the use of senescent cell-depleting agents, or senolytics, has been shown to improve the aging phenotype in animal models. Since senescence has been implicated in the skin, particularly in fibroblasts, this study used aged human skin fibroblasts to investigate the effects of resibufogenin.

A component of the traditional Chinese medicine toad venom, resibufogenin was investigated for senolytic and/or senomorphic activity. We found that the compound selectively caused senescent cell death without affecting proliferating cells, with a marked effect on the suppression of the senescence-associated secretory phenotype. We also found that resibufogenin causes senescent cell death by inducing a caspase-3-mediated apoptotic program. Administration of resibufogenin to aging mice resulted in an increase in dermal collagen density and subcutaneous fat, improving the phenotype of aging skin. In other words, resibufogenin ameliorates skin aging through selective induction of senescent cell apoptosis without affecting non-aged cells. This traditional compound may have potential therapeutic benefits in skin aging characterized by senescent cell accumulation.

Diastolic function is controlled by active relaxation of cardiomyocytes and passive stiffness of the myocardium. Cardiomyocyte relaxation is controlled by the interplay of two macromolecular systems: membrane bound Ca2+ handling proteins to send the signal to start and stop contraction, and sarcomeric proteins for force generation and contraction regulation by Ca2+. Passive stiffness of the myocardium is controlled by mechanisms such as extracellular matrix remodeling, titin isoform shift and titin phosphorylation. It has been shown that rapamycin reduces the age-related increase in passive stiffness of the myocardium. The effects of rapamycin on active cardiomyocyte relaxation and the precise molecular mechanisms of rapamycin mediated reduction in passive myocardial stiffness remain unknown. Identifying the mechanisms by which rapamycin improves diastolic function in the aging heart will advance our understanding on its therapeutic potentials in cardiac aging and heart failure with preserved ejection fraction (HFpEF).

To dissect the mechanisms by which rapamycin improves diastolic function in old mice, we examined the effects of rapamycin treatment at the levels of single cardiomyocyte, myofibril, and multicellular cardiac muscle. Compared to young cardiomyocytes, isolated cardiomyocytes from old control mice exhibited prolonged time to 90% relaxation (RT90) and time to 90% Ca2+ transient decay (DT90), indicating slower relaxation kinetics and calcium reuptake with age. Late-life rapamycin treatment for 10 weeks completely normalized RT90 and partially normalized DT90, suggesting improved Ca2+ handling contributes partially to the rapamycin-induced improved cardiomyocyte relaxation.

In addition, rapamycin treatment in old mice enhanced the kinetics of sarcomere shortening and Ca2+ transient increase in old control cardiomyocytes. Myofibrils from old rapamycin-treated mice displayed increased rate of the fast, exponential decay phase of relaxation compared to old controls. The improved myofibrillar kinetics were accompanied by an increase in MyBP-C phosphorylation following rapamycin treatment. We also showed that late-life rapamycin treatment normalized the age-related increase in passive stiffness of demembranated cardiac trabeculae through a mechanism independent of titin isoform shift. In summary, our results showed that rapamycin treatment normalizes the age-related impairments in cardiomyocyte relaxation, which works conjointly with reduced myocardial stiffness to reverse age-related diastolic dysfunction.

Bayer AG and BlueRock Therapeutics LP, a clinical stage cell therapy company and wholly owned independently operated subsidiary of Bayer AG, today announced positive top-line results from a Phase I clinical trial of investigational drug, bemdaneprocel (BRT-DA01), a potential first-in-class cell therapy for Parkinson's disease. The trial showed that bemdaneprocel was well-tolerated in all 12 patients in the study to date, with no major safety events. In addition, an assessment of the study's secondary endpoints demonstrated feasibility of transplantation and evidence of cell survival and engraftment in the brain through one year. Based on these results, planning is underway for a Phase II study that is expected to begin enrolling patients in H1 (first half) 2024.

Bemdaneprocel (BRT-DA01), an investigational therapy comprised of dopamine producing neurons derived from pluripotent stem cells, is surgically implanted into the brain of a person with Parkinson's disease. When transplanted, these cells have the potential to reform neural networks that have been destroyed by Parkinson's disease in the hope of restoring motor and non-motor function to patients. The primary objective of the Phase I trial is to assess the safety and tolerability of bemdaneprocel (BRT-DA01) transplantation at one-year post-transplant. The secondary objectives of the trial are to assess the evidence of transplanted cell survival and motor effects at one- and two-years post-transplant, to evaluate continued safety and tolerability at two years, and to assess feasibility of transplantation.

Longevity is written into the genes. While many so-called "longevity genes" have been identified, the reason why particular genetic variants are associated with longer lifespan has proven to be elusive. The aim of the present study was to test the hypothesis that the strongest of 3 adjacent longevity-associated single nucleotide polymorphisms - rs3794396 - of the vascular endothelial growth factor receptor 1 gene, FLT1, may confer greater lifespan by protecting against mortality risk from one or more adverse medical conditions of aging - namely, hypertension, coronary heart disease (CHD), stroke, and diabetes.

In a prospective population-based longitudinal study we followed 3,471 American men of Japanese ancestry living on Oahu, Hawaii, from 1965 until death or to the end of December 2019 by which time 99% had died. Cox proportional hazards models were used to assess the association of FLT1 genotype with longevity for 4 genetic models and the medical conditions. We found that, in major allele recessive and heterozygote disadvantage models, genotype GG ameliorated the risk of mortality posed by hypertension, but not that posed by having CHD, stroke, or diabetes. Normotensive subjects lived longest and there was no significant effect of FLT1 genotype on their lifespan.

In conclusion, the longevity-associated genotype of FLT1 may confer increased lifespan by protecting against mortality risk posed by hypertension. We suggest that FLT1 expression in individuals with longevity genotype boosts vascular endothelial resilience mechanisms to counteract hypertension-related stress in vital organs and tissues.

Physical exercise has beneficial effects by providing neuroprotective and anti-inflammatory responses to Alzheimer's disease (AD). Most studies, however, have been conducted with aerobic exercise, and few have investigated the effects of other modalities that also show positive effects on AD, such as resistance exercise (RE). In addition to its benefits in developing muscle strength, balance and muscular endurance favoring improvements in the quality of life of the elderly, RE reduces amyloid load and local inflammation, promotes memory and cognitive improvements, and protects the cortex and hippocampus from the degeneration that occurs in AD.

Therefore, the aim of this study was to investigate the effects of 4 weeks of RE intermittent training on the prevention and recovery from these AD-related neuropathological conditions in APP/PS1 mice. For this purpose, 6-7-month-old male APP/PS1 transgenic mice and their littermates, negative for the mutations (Control), were distributed into three groups: Control, APP/PS1, APP/PS1+RE. RE training lasted four weeks and, at the end of the program, the animals were tested in the open field test for locomotor activity and in the object recognition test for recognition memory evaluation. The brains were collected for immunohistochemical analysis of Aβ plaques and microglia, and blood was collected for plasma corticosterone by ELISA assay.

APP/PS1 transgenic sedentary mice showed increased hippocampal Aβ plaques and higher plasma corticosterone levels, as well as hyperlocomotion and reduced central crossings in the open field test, compared to APP/PS1 exercised and control animals. The intermittent program of RE was able to recover the behavioral, corticosterone and Aβ alterations to the Control levels. In addition, the RE protocol increased the number of microglial cells in the hippocampus of APP/PS1 mice. Altogether, the present results suggest that RE plays a role in alleviating AD symptoms, and highlight the beneficial effects of RE training as a complementary treatment for AD.

In recent years, researchers have attempted to counteract aging using senotherapeutics that selectively target senescent cells. Senotherapeutics are categorized into two groups. Senolytic drugs selectively eliminate senescent cells, and senomorphic drugs inhibit the negative effects of their SASP. Since the combination of dasatinib and quercetin was proposed as the first senolytic drug to suppress genes that are increased in senescent cells, many studies have shown that various substances such as ABT-737, ABT-263, A1155463, and fisetin have anti-aging properties.

In particular, ABT-263 and ABT-737, which are Bcl-2 inhibitors, have been found to selectively eliminate SA β-gal-positive senescent cells in skin both in vitro and ex vivo. Researchers demonstrated that either ABT-263 or ABT-737 treatment selectively eliminated dermal fibroblasts in an intrinsic skin aging mouse model. They also showed that the treatment increased the collagen density, epidermal thickness, and keratinocyte proliferation while reducing SASPs including MMP-1 and IL-6. Further, the team revealed that treatment with ABT-263 and ABT-737 also attenuated the induction of MMPs and decreased collagen density in the photoaging mouse model. In addition, ABT-263 showed potential in reducing pigmentation caused by photoaging in human skin inducing apoptosis of p16INK4A-positive fibroblasts with its senolytic activity, resulting in decreased levels of melanin and tyrosinase activity.

One of the most notable targets of senomorphic agents is the mechanistic target of rapamycin (mTOR) pathway, which regulates cellular metabolism and is linked to cellular growth, proliferation, and autophagy. The mTOR pathway is also involved in the synthesis of SASP. Rapamycin, an mTOR inhibitor, exhibited significant reduction in senescence markers and SASP as well as oxidative stress in UV-induced photoaged human dermal fibroblasts. Moreover, researchers revealed the potential anti-aging effect of topical application of rapamycin (an mTOR inhibitor). A total of 17 subjects over the age of 40 years with age-related photoaging of the skin applied a rapamycin-containing hand cream to the dorsum of one hand and a placebo hand cream to the other hand daily for 8 months and found that the rapamycin-treated hand had a decrease in p16 and an increase in collagen VII protein.

Taken together, these promising results suggest that senotherapeutics may be a novel therapeutic option for skin aging; however, the limitations of these drugs, such as their specificity, selectivity, and efficiency, still need to be addressed, and their mechanisms of action and side effects must be better understood.

Cardiovascular diseases (CVD) are the leading cause of hospitalization and death globally. CVD includes disturbances of the heart rhythm, cardiac valve pathologies, genetically driven malformations and, ultimately, peripheral artery disease (PAD) or coronary artery disease (CAD), which may culminate, respectively, in critical limb ischemia (CLI) and heart failure (HF). The use of cells with stem/progenitor characteristics in PAD and CLI has shown a success in clinical translation to a certain extent, given the ability of the chosen cells (e.g., derived from bone marrow, peripheral blood, or cord blood) to promote de novo vasculogenesis by a robust "paracrine effect". By contrast, the use of a similar setting to regenerate the contractile mass of the heart to compensate the loss of myocytes due to acute/chronic ischemia and/or inflammation has been largely unsuccessful and controversial, due to the absence of resident stem cells that could be activated in situ and/or expanded in vitro prior to being reinjected into the failing hearts.

Alternatives to this deficiency have been sought in the use of induced pluripotent stem cells (iPSCs), whose derived cardiomyocytes (CMs) have been employed in preclinical models in small and large animals, and even in pioneering studies in humans. Although scaled-up systems to produce therapeutic quantities of these cells with enhanced purity have been set, anticipating industrial production, several caveats have been expressed due to risks of arrhythmogenicity, incomplete maturation, potential tumor formation, and (at least for allogenic use) immune reactions.

Given the lack of endogenous regenerative capacity of the myocardium, the consequence of acute/chronic cardiac ischemia is still considered an irreparable damage leading to progressive replacement of the contractile cells with a stiff, fibrotic scar. Under these conditions, the heart undergoes a series of morphological transformations (e.g., rearrangement of the contractile apparatus and modification of the geometry), changes in mechanical characteristics and reduction of the pumping efficiency, representing signs of HF. With the advent of tissue engineering, the introduction of biological fabrication methods combined with refined systems for cellular genetic manipulation and decryption of mechanosensitive cues has enabled new strategies to enhance the efficacy of cardiac cell therapy and the elaboration of disease modeling systems using scaffolds, tissue printing, and tissue engineering approaches. This renews the hope that after the disappointment arising from the failure of the "classical" cell therapy approaches, it will be possible to reach a condition to regenerate the human heart, which still represents the "holy grail" of cardiology.

Age is the greatest risk factor for adverse outcomes following influenza infection. The increased burden of senescent cells with age has been identified as a root cause in many diseases of aging and targeting these cells with drugs termed senolytics has shown promise in alleviating many age-related declines across organ systems. However, there is little known whether targeting these cells will improve age-related deficits in the immune system.

Here, we utilized a well characterized senolytic treatment with a combination of dasatinib and quercetin (D + Q) to clear aged (18-20 months) mice of senescent cells prior to influenza infection. We comprehensively profiled immune responses during the primary infection as well as development of immune memory and protection following pathogen reencounter. Senolytic treatment did not improve any aspects of the immune response that were assayed for including: weight loss, viral load, CD8 T-cell infiltration, antibody production, memory T cell development, or recall ability. These results indicate that D + Q may not be an appropriate senolytic to improve aged immune responses to flu infection.

It was traditionally believed that the lymphatic system didn't exist in the central nervous system. Thus, cell debris, potential neurotoxic proteins, and other metabolites with large molecular weight were considered to be removed in a different clearance pathway than brain vasculature. In 2012, the researchers found that cerebrospinal fluid (CSF) can enter brain parenchyma and exchange with brain interstitial fluid (ISF) in the presence of aquaporin-4 (AQP4) on astrocytes. Likewise, when the mixed fluid was drained from the brain, Amyloid-β (Aβ) was transported along with the outflow. Since the function of this "drainage" pathway is similar to that of the lymphatic system and supported by astrocytes, it was named the glymphatic system after the role of glia cells.

Since last decade, many researchers in the field of neurology, neurodegenerative diseases and physiology have aimed to study and develop the glymphatic system, providing a brand-new perspective for us to understand brain diseases: the overall fluid flow of the brain rather than a specific lesion or structure. Herein, we summarized the components of the glymphatic system, the fluid circulation mode within this system, how pathogenic solutes are transported in certain diseases, affecting factors of its function, and by what means we can study the glymphatic system. It may provide direction and reference for brain diseases and medical researchers.

It is evident that microglia are crucial players in the pathogenesis of Alzheimer's disease (AD), and a deeper understanding of their diverse functions and interactions with other cellular components in the brain will be vital for the development of effective therapeutic strategies. However, despite considerable progress in recent years, there remain significant gaps in our knowledge of microglial biology, particularly concerning their heterogeneity, precise mechanisms of action, and the interplay between various signaling pathways.

Multiple research studies have underscored the significance of specific subsets of microglia, particularly disease-associated microglia (DAM), in the progression of AD. The conjecture underpinning microglial depletion is that certain activated microglia, including DAM, may accentuate AD pathogenesis through a series of actions, such as facilitating the accumulation of Aβ plaques, amplifying neuroinflammation, and potentially influencing tau pathology. DAMs, characterized by a unique transcriptional profile and often found in close proximity to amyloid plaques, are thought to have substantial impacts on neuronal health and function. Consequently, it has been proposed that therapeutic strategies should be more disease-specific and aim at selectively targeting these DAMs.

The implementation of microglial depletion has been achieved through various strategies, most notably using pharmacological and genetic techniques. A common method involves the use of brain-penetrating inhibitors of CSF1R, a crucial cell surface receptor for microglial survival and proliferation. In AD mouse models, these inhibitors have demonstrated improvements in cognition and reductions in both neuroinflammation and neuritic plaque formation. However, the relationship between microglial depletion and amyloid pathology has been inconsistent, highlighting the need for further investigation. The potential of microglial depletion as a therapeutic approach must be carefully evaluated, but more research is warranted to further elucidate the complex roles of microglia, particularly DAM, in AD pathogenesis and treatment.

Aging is an inevitable life process. The ability of aging organs to resist adverse external stimuli decreases, and thus they are more vulnerable to damage. Mitochondrial homeostasis plays an indispensable role in maintaining kidney function, and when mitochondrial function is disturbed, it will accelerate the aging of renal cells. Here, we reviewed the evidence of renal mitochondrial disorders, including abnormal mitochondrial function, abnormal mitophagy, and abnormal activation of oxidative stress and inflammation in renal aging.

Although targeting mitochondria is a potential strategy to slow kidney aging, many questions remain to be addressed, such as what role mitochondrial DNA (mtDNA) plays in renal aging. Although current studies have shown that inhibiting the release of mtDNA can inhibit the activation of inflammation and the occurrence of aging in other tissues and cells, there has been no research on the role of mtDNA in renal aging. Moreover, identifying specific renal mitophagy activators is also needed. Current studies have been conducted on animal and cell models, and there may be significant differences in the aging process and immune system between species that could limit the applicability of these findings to humans. Therefore, the relationship between aging and mitochondrial abnormalities in kidney tissue needs to be clarified in future studies.

When these questions are thoroughly investigated and answered, targeting mitochondria as a strategy to alleviate kidney aging will be viable. In addition, given the importance of mitochondria in biological activity and aging, targeting mitochondria may be a strategy for delaying aging in organs other than the kidney.

"The thymus had largely been ignored because it's complicated, and historically understanding of the biology had progressed slowly. It's starting to accelerate now and a lot of the work that the Francis Crick Institute has been doing is aimed at understanding the core stem cell niche of the thymus and use this to recreate thymus biology. Until recently, there was uncertainty around the progenitor stem cell that leads to the epithelial cells that gives the thymus function. The Crick researchers discovered novel progenitor cells and Videregen has licensed the resulting patents, which give us the basis of the cell biology. That allows us to build a better functioning thymus from scratch, because we understand the cell biology better than anyone else."

The initial indication for Videregen's immune program is children born without thymus function, which is called complete DiGeorge Syndrome, but this is only the beginning of the company's work in this area. "The thymus is primarily concerned with two things: the first is to provide T cells, which fight infection and circulate our bodies throughout our life, taking out precancerous cells. Over time, our thymus function decreases, which is why in old age, you tend to get more cancers, you respond less well to vaccines, and you get more infections. So addressing thymus atrophy is a big factor in longevity and aging. At the moment, we're focusing on niche, orphan indications, which means we don't need to industrialize to a big scale - we're talking about hundreds or thousands of patients, not millions. But when we get to those kinds of scales of populations, we will need the technology to be able to deliver a mass-produced tissue."

Videregen's approach is built on the company's expertise in decellularization - the process used to isolate the extracellular matrix of a tissue from its inhabiting cells, leaving only a "scaffold" of the original tissue. This scaffold can then be seeded with appropriate cells to enable organ and tissue regeneration. "We've learned that the biology of the extracellular matrix is really important - it isn't just structural. If you preserve the biology well, you get better infiltration of cells, better vascularization, and better repair and function over time. This is achieved by controlling the way the tissue is processed and decellularized - the more natural the better."