Fight Aging!

Greater personal wealth very clearly correlates with modestly greater longevity. Why is this? That is a hard question to answer, as the network of correlations between socioeconomic status, education, wealth, intelligence, and lifestyle choices are challenging to pick apart in most available databases of epidemiological information. Are wealthier people on balance more educated, and more educated people tend to take better care of their health? Are wealthier people wealthy because they tend to be more proactive in all aspects of life, and thus also make better use of the opportunities provided by medical technology? Are wealthier people better equipped culturally by their upbringing to take better care of their health? Does greater intelligence, and thus greater capacity to become wealthy, derive from gene variants that also produce physical robustness and a longer life span? And so forth.

The study here is interesting for looking into the correlation between personal wealth and the later life survival of siblings and twins, as well as a more general population. Comparing siblings can eliminate many of the questions regarding, for example, the effects of upbringing in a wealthier environment on lifestyle choice, or the possibility of pleiotropic effects of genetic variants on both intelligence and physical robustness. The researchers find that wealth effects on longevity, whatever the underlying cause, appear to be much the same between siblings and non-siblings. This by no means points to a definitive explanation for the correlations observed, but it does make some of the existing hypotheses less likely to be true.

Association of Wealth With Longevity in US Adults at Midlife

Socioeconomic disparities in life expectancy are substantial in size. Financial wealth or net worth, which is the value of an individual's assets (such as savings, real estate, and vehicles) minus liabilities, is directly associated with longevity. However, a challenge in this area of research has been eliminating or minimizing the potential for confounding by the early environment and heritable traits, either of which could simultaneously affect socioeconomic conditions in adulthood and health in the course of life.

Full siblings who were raised in the same family share much of their early rearing environment and are genetically related to one another. Thus, in sibling-comparison studies, factors that are shared between siblings are controlled. Twin comparisons provide an even greater control of family-level early-life confounding and, in the case of monozygotic (MZ) twins, control for all heritable genetic factors. Previous research found that discordance in occupational prestige was associated with cardiovascular risk and overall mortality; twins with lower-prestige jobs had worse health on both outcomes compared with their co-twins with higher-prestige jobs. This pattern suggests that socioeconomic disparities in health are affected by experiential factors in adulthood over and above any potential confounders that involve the siblings' shared early environment and genetic characteristics. In other discordant sibling and twin analyses, educational attainment and composite measures of adult socioeconomic position also have been associated with better adult health outcomes and longevity. However, results from these and other studies that used different methods do suggest these associations may be partially explained by shared family-level environmental factors or genetic predispositions.

Comparatively little attention has been given to wealth disparities, a potentially important oversight. In this cohort study, we used a discordant sibling design to conservatively estimate the association between wealth and longevity. Specifically, we aimed to identify the association between net worth at midlife (the middle years of life) and subsequent all-cause mortality in individuals as well as within siblings and twin pairs. We posed two research questions. First, was wealth accumulation at midlife associated with longevity over a nearly 24-year follow-up? Consistent with previous work, we expected that higher wealth accumulation would be associated with increased longevity. Second, was the wealth-longevity association present over and above controls for family and heritable factors that could confound this association?

In this cohort study of 5,414 participants in the Midlife in the United States study, those who had accumulated a higher net worth by midlife had significantly lower mortality risk over the subsequent 24 years. In sibling and twin comparison models that controlled for shared early life experiences and genetic influence, the association between net worth and longevity was similar in magnitude. Thus net worth at midlife was associated with longevity among adults in the study, and this association is unlikely to be merely an artifact of early experiences or heritable traits shared by families.

Osteoporosis is more prevalent in older women than in older men, for reasons related to estrogen deficiency, but the detailed mechanisms remain less clear than clinicians would like them to be. Many aspects of aging are correlated with one another. Aging is a burden of damage and consequences of that damage, progressing at modestly different paces in different individuals, largely due to variations in lifestyle choices and environmental exposure to persistent pathogens. Genetics plays some role, but probably only a small role in near all people. Thus more damage gives rise to a greater risk of many different age-related conditions in the same individual. Still, in some cases, one condition can contribute directly to another. For example, to the extent that osteoporosis restricts activity (and thus vascular health, cerebral blood flow, and so forth), it will likely harm cognitive health over time.

Dementia and osteoporosis are highly prevalent in the elderly population and often coexist. Individuals with dementia are at high risk of osteoporosis and hip fracture. It has been estimated that approximately 40% of patients with hip fracture have a prior diagnosis of dementia. The risk of hip fracture in Alzheimer's disease was recently reported in a meta-analysis of nine cohorts from the United States, Canada, and the UK to be over twofold compared to those without dementia. Furthermore, this study also demonstrated that hip bone mineral density (BMD) was lower in those affected compared to controls.

Notably, a recent study has demonstrated increased risk of dementia following both hip and non-hip fractures. Although the risk of dementia was highest following hip fracture (60%), vertebral (47%), lower (35%), and upper limb (29%) fractures were also associated with increased risk. These findings are particularly important as non-hip fractures are very common, affecting two in five women and one in three men after the age of 60 years.

The nature of the association between osteoporosis and dementia is not entirely clear. Most authors to date believe that the association between these two common conditions is likely driven by common risk factors such as old age, sedentary lifestyle, physical decline, vitamin D insufficiency, sarcopenia, and propensity to falls. However, there is some evidence that suggests that hip fracture per se may lead to complications which directly precipitate dementia development. Furthermore, at least two studies have shown a significant association between low BMD or bone loss and subsequent cognitive decline in postmenopausal women. However, studies investigating the longitudinal long-term association between cognitive decline and both bone loss and fracture risk are lacking.

This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Over 95% of participants had normal cognition at baseline. After multivariable adjustment, cognitive decline was associated with bone loss in women but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly. There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women

Link: https://doi.org/10.1002/jbmr.4402

Calorie restriction is perhaps the most studied of all interventions known to slow aging, and yet undergoing calorie restriction changes so much of metabolism that it remains a challenge to understand which of the countless mechanisms involved are important. It is clearly the case that the cellular maintenance processes of autophagy are critical, as researchers have shown that when autophagy is sabotaged via genetic engineering, calorie restriction no longer produces its well-known benefits to health and longevity. Beyond that, different research groups peer intently at very localized portions of cell and tissue biochemistry, and seem likely to continue doing that well into the era in which calorie restriction, and the entire concept of slowing aging via metabolic adjustment, is surpassed by rejuvenation therapies based on periodic repair of the molecular damage that causes aging.

Endothelin-1 (ET-1) is a potent vasoconstrictor synthesized by vascular endothelial cells that is normally present at low plasma concentrations. ET-1 plays a significant role in kidney physiology and pathology, highlighted by the fact that ET-1 transgenic mice undergo spontaneous kidney fibrosis even in the absence of hypertension. Ageing is associated with an increase in ET-1 levels in the renal vasculature. Elevated ET-1 can increase reactive oxygen species (ROS), which in turn can increase the uptake of oxidized low-density lipoprotein (ox-LDL) by increasing the expression of its cognate receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), cumulatively contributing to endothelial dysfunction. Indeed, pre-clinical studies with endothelin receptor antagonists have shown promising results in alleviating ageing-induced impairment of renal function.

Caloric restriction (CR) can reduce the ageing process and related organ dysfunction in most species. CR without malnutrition is a dietary regimen that delays ageing and extends the lifespan. More importantly, studies in mice and rat models of ageing have shown that CR exerts significant cerebrovascular protective effects, improves cortical microvascular density and endothelial function, and counteracts ageing-induced alterations in renal function, including glomerulosclerosis and alterations in glomerular filtration. CR also improved vascular health by eliciting changes in the levels of circulating neuroendocrine factors.

Given this background, the objective of the current study was to investigate whether CR counteracts ageing-induced alterations in renal function and inflammatory cytokines by impacting ET-1 levels. We found that ET-1 messenger RNA (mRNA) and protein expression were increased ex vivo in the renal artery segments of 12-month-old rats compared to 2-month-old rats, which was reversed when rats were subjected to CR. Functional assays showed that CR alleviated renal dysfunction and decreased the expression of pro-inflammatory cytokines by decreasing ET-1 expression.

Link: https://doi.org/10.21037/atm-21-2218

Parkinson's disease is the best known of the synucleinopathies, age-related neurodegenerative conditions characterized by the damaging aggregation of misfolded α-synuclein. This is one of only a few proteins in the body that can misfold in ways that encourage other molecules of the same protein to also misfold, creating a contagion that can slowly spread from cell to cell, and aggregate into toxic structures that disrupt cell function and kill cells.

Today's research materials examine some of the details of the spread of misfolded α-synuclein. This is an important topic for the same reasons that metastasis of cancer is an important topic. Finding ways to prevent the spread to neighboring tissue would remove the worse aspects of both cancer and synucleinopathies, restricting them to localized harm. This requires a comprehensive exploration of the biochemistry involved, as a priori it is hard to say which of the presently unknown or poorly understood details will turn out to be useful.

It has become clear in recent years that mammalian cells can and do exchange component parts with one another. There is considerable evidence for the transfer of mitochondria, for example. Cells with functional mitochondria have been observed attempting to rescue cells with damaged mitochondria, extending structures called tunneling nanotubes that link two cells together, and passing mitochondria through that connection. Here, researchers observe cells doing this in order to transfer lysosomes, which act as recycling units in cells, responsible for breaking down damaged and unwanted molecules. The misfolding of α-synuclein hijacks this process in a way that favors transmission of misfolded proteins between cells, carried within damaged lysosomes.

Parkinson's disease: how lysosomes become a hub for the propagation of the pathology

The accumulation of misfolded protein aggregates in affected brain regions is a common hallmark shared by several neurodegenerative diseases (NDs). Mounting evidence in cellular and in animal models highlights the capability of different misfolded proteins to be transmitted and to induce the aggregation of their endogenous counterparts, this process is called "seeding". In Parkinson's disease, the second most common ND, misfolded α-synuclein (α-syn) proteins accumulate in fibrillar aggregates within neurons. Those accumulations are named Lewy bodies.

In 2016, a team of researchers demonstrated that α- syn fibrils spread from donor to acceptor cells through tunneling nanotubes (TNTs). They also found out that these fibrils are transferred through TNTs inside lysosomes. Following this original discovery, researchers now shed some light on how lysosomes participate in the spreading of α-syn aggregates through TNTs. "By using super-resolution and electron microscopy, we found that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. We demonstrated for the first time that α-syn fibrils induce the peripheral redistribution of the lysosomes thus increasing the efficiency of α-syn fibrils' transfer to neighbouring cells."

They also showed that α-syn fibrils can permeabilize the lysosomal membrane, impairing the degradative function of lysosomes and allowing the seeding of soluble α-syn, which occurs mainly in those lysosomes. Thus, by impairing lysosomal function α-syn fibrils block their own degradation in lysosomes, that instead become a hub for the propagation of the pathology.

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a "prion-like" manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils' transfer to neighboring cells.

We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them.

These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

The results reported here are intriguing, suggesting that some aspects of the extracellular matrix structure in the brain are of great importance to neural plasticity loss of memory function with age, at least in mice. This is quite novel. Most work on neurodegeneration touches only lightly, if at all, on the structure and composition of the extracellular matrix. Researchers here used a gene therapy to adjust the proportion of different chondroitin sulphates in matrix structures in old mice, and the resulting restoration of memory function is quite impressive.

Recent evidence has emerged of the role of perineuronal nets (PNNs) in neuroplasticity - the ability of the brain to learn and adapt - and to make memories. PNNs are cartilage-like structures that mostly surround inhibitory neurons in the brain. Their main function is to control the level of plasticity in the brain. They appear at around five years old in humans, and turn off the period of enhanced plasticity during which the connections in the brain are optimised. Then, plasticity is partially turned off, making the brain more efficient but less plastic.

PNNs contain compounds known as chondroitin sulphates. Some of these, such as chondroitin 4-sulphate, inhibit the action of the networks, inhibiting neuroplasticity; others, such as chondroitin 6-sulphate, promote neuroplasticity. As we age, the balance of these compounds changes, and as levels of chondroitin 6-sulphate decrease, so our ability to learn and form new memories changes, leading to age-related memory decline.

Researchers investigated whether manipulating the chondroitin sulphate composition of the PNNs might restore neuroplasticity and alleviate age-related memory deficits. To do this, the team looked at 20-month old mice - considered very old - and using a suite of tests showed that the mice exhibited deficits in their memory compared to six-month old mice. The team treated the ageing mice using a 'viral vector', a virus capable of reconstituting the amount of 6-sulphate chondroitin sulphates to the PNNs and found that this completely restored memory in the older mice, to a level similar to that seen in the younger mice.

Link: https://www.cam.ac.uk/research/news/scientists-reverse-age-related-memory-loss-in-mice

Frailty is a condition with a strong inflammatory component. It isn't just physical weakness, but also the vulnerability of an incapable and constantly overactive immune system, generating inflammatory signaling that disrupts tissue and organ function throughout the body. In recent years, there has been a considerable growth of interest in the gut microbiome and its contribution to aging. It is clear that microbial populations shift with age in ways that promote inflammatory engagement with the immune system. Replacing an old gut microbiome with a young gut microbiome, such as via fecal microbiota transplantation, produces a reduction in inflammation, improvement in function, and extension of life span in short-lived animal models. This is an approach to rejuvenation that could be fairly rapidly developed for human use, and certainly should receive more attention and funding than is presently the case.

Frailty is a clinical syndrome characterized by "diminished strength, endurance, and reduced physiological function". Frailty predisposes patients to negative health-related outcomes such as falls, hospitalization, disability, dependency, and mortality. The prevalence of frailty ranges from 4% to 59% in community-dwelling older adults and increases with age. Given the rapidly aging population, the United Nations estimates that worldwide, the number of people aged 60 years and above will double to nearly 2.1 billion by 2050. Therefore, frailty is a pressing concern in aging societies.

Microorganisms, as an environmental factor, are among the most interesting contributors to aging, and they provide a new perspective in understanding the aging process. As a person ages, progressive changes in intestinal tract physiology, the intestinal mucosal immune system, lifestyle changes (particularly in diet and exercise), medication, malnutrition, inflammation, and immune senescence may change the diversity, composition, and functional features of the gut microbiota. Data from animal models demonstrate that age-related microbial dysbiosis contributes to intestinal permeability, systemic inflammation, and premature mortality. Though the cause-and-effect relationship is unclear, age-related microbial dysbiosis is linked to unhealthy aging and geriatric syndromes, which include frailty. Identifying specific changes in frailty-related gut microbiota is essential in developing microbiome-based diagnostic and therapeutic strategies.

In this review, we first describe the relevant changes in gut microbiota related to aging and frailty. Subsequently, we summarize recent findings on the possible role of chronic low-grade inflammation in frailty and how microbial dysbiosis is involved in its pathogenesis, including frailty-related inflammation.

Link: https://doi.org/10.3389/fcimb.2021.675414

An interesting body of scientific work exists to investigate the question of whether or not various forms of electromagnetic stimulation can improve tissue function, particularly in older people. To improve neurogenesis in an aging brain, or enhance nerve regrowth following injury, for example. Taken broadly, the manipulation of cells to specific ends via electromagnetism is far less studied than is the case for the use of small molecules, however, and this is very evident in the character of the data.

Picking any one approach to electromagnetic therapy at random, one tends to find unpromising results, when taken as a whole, meaning a few flashes of claimed success amidst a great deal of failure. There is reason to believe that the fine details of equipment, experimental setup, duration of treatment, and frequency of electromagnetic radiation are all important, and that perhaps consistent success is a matter of finding the right combination for a given application. That may or may not be the case.

Transcranial direct current stimulation has the merit of having perhaps fewer important variables to adjust in terms of how the treatment is delivered, which might explain why the data looks somewhat better for this approach than for others I've seen. That is a low bar, but still. Today's open access paper provides a review of the literature on this topic, which at the end of the day suggests that some approaches can beneficially affect at least some functions in the aging brain. Considerable uncertainty remains.

Can Transcranial Direct Current Stimulation Enhance Functionality in Older Adults? A Systematic Review

Transcranial direct current stimulation (tDCS) is a non-invasive tool for neuromodulation that has proven to be well-tolerated and safe. This technique employs low-intensity continuous or galvanic current applied transcutaneously via electrodes placed on the scalp. The change generated in the electric potential of the membrane of the underlying neurons affects neuronal excitability, which varies depending on the orientation of the electric field determined by the position and polarity of the electrodes. This effect on excitability is believed to be related to transient changes in the synaptic efficiency of different neurotransmitters.

Complex structural and functional changes in the brain are some of the processes related to normal aging that entail deterioration of cognitive, perception, and motor capacities, which affects daily life activities, independence, and quality of life. The main finding observed is the increase in dual-task costs, and the most affected ability due to aging is the simultaneous execution of one motor and one cognitive task. Additionally, older adults present a reduction in the structural and functional plasticity of the brain and in flexibility for tasks requiring previous learning. Trials using neuroimaging indicate that the left dorsolateral prefrontal cortex (DLPFC), which intervenes in the executing function, is one of the key brain regions involved in performing combined cognitive and motor tasks under dual-task conditions. For this reason, tDCS interventions designed for facilitating the functional activation of the DLPFC and its neuronal networks could improve the cognitive function and motor performance in the elderly.

This systematic review aimed at compiling and summarizing the currently available scientific evidence about the effect of tDCS on functionality in older adults over 60 years of age. A search of databases was conducted to find randomized clinical trials that applied tDCS versus sham stimulation in the above-mentioned population. No limits were established in terms of date of publication. A total of 237 trials were found, of which 24 met the inclusion criteria. Finally, nine studies were analyzed, including 260 healthy subjects with average age between 61.0 and 85.8 years. Seven of the nine included studies reported superior improvements in functionality variables following the application of tDCS compared to sham stimulation. Anodal tDCS applied over the motor cortex may be an effective technique for improving balance and posture control in healthy older adults. However, further high-quality randomized controlled trials are required to determine the most effective protocols and to clarify potential benefits for older adults.

Intermittent fasting strategies, such as alternate day fasting, are known to slow aging in a variety of species. The mechanisms are likely similar to those involved in the calorie restriction response, meaning upregulation of stress responses and cellular maintenance, though intermittent fasting is capable of producing some degree of benefits even when overall calorie intake is not reduced. Time spent in a state of hunger, and the consequent reactions of cells and tissues, is clearly an important factor. The human data for both calorie restriction and intermittent fasting shows health benefits, and from what is known of the mechanisms involved it is reasonable to propose that calorie restriction or intermittent fasting could modestly slow at least some forms of neurodegenerative condition.

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting ~2% of the population over age 70. Disease prevalence increases with age and, given the aging population, may triple in the next few years. The neurodegenerative mechanism leading to PD is still not completely elucidated. Alpha-synuclein may drive the neurodegenerative process of PD. When aggregated in neurons as intracellular Lewy bodies, it constitutes the pathologic hallmark of PD. On the other hand, mitochondrial dysfunction, oxidative stress, and selective neuronal loss each contribute to PD pathology.

Unfortunately, there remains no disease-modifying treatment in PD despite multiple trials of promising preclinical targets. Supplements and dietary interventions have been periodically considered as possible therapeutic approaches to impact disease progression and severity in related neurodegenerative disorders. One such intervention is intermittent fasting (IF). This viewpoint seeks to describe the putative pathophysiologic relationships among mitochondria, alpha-synuclein, and PD risk genes, and to provide a background for the rationale or the use of IF and similar mitochondrial-targeting therapies in PD. Finally, we propose an outline for determining the efficacy of an IF intervention in PD.

Link: https://doi.org/10.3389/fneur.2021.682184

When faced with long-lasting challenges, such as cancer or persistent infections that the immune system struggles to clear, T cells of the adaptive immune system can become exhausted. The exhausted cells lose function, diminishing both the immediate immune response and the ability to form immune memory that will enable a robust future response to the same threat. Researchers see this in the engineered T cells used in chimeric antigen receptor (CAR) T cell therapies, and there is thus a strong incentive to find ways to address the issue by identifying important causes or regulators of T cell exhaustion, and interfering to prevent it.

Fighting a tumor is a marathon, not a sprint. For cancer-fighting T cells, the race is sometimes just too long, and the T cells quit fighting. Researchers even have a name for this phenomenon: T cell exhaustion. Researchers now report that T cells can be engineered to clear tumors without succumbing to T cell exhaustion. This research builds on work that has shown the key role of proteins called transcription factors in the cellular pathway that triggers T cell exhaustion. This work is important because T cell exhaustion continues to plague even the most cutting-edge cancer immunotherapies.

With CAR T therapies, for example, researchers take T cells from a cancer patient and "arm" them by altering the expression of genes that aid in the cancer fight. Researchers make more of these special T cells, which then go back into the patient. CAR T therapies are different from immunotherapies, which aim to activate the patient's existing T cell population. With both approaches, T cell exhaustion rears its ugly head. "Many people have tried to use CAR T therapies to kill solid tumors, but it's been impossible because the T cells become exhausted."

The new study addresses this problem by giving T cells the ability to fight exhaustion itself. To accomplish this, the researchers screened T cells to uncover which transcription factors could boost a T cell's "effector" program, an important step in readying T cells to kill cancer cells. This screening process led the researchers to BATF, a transcription factor that they found cooperates with another transcription factor called IRF4 to counter the T cell exhaustion program.

In mouse melanoma and colorectal carcinoma tumor models, altering CAR T cells to also overexpress BATF led to tumor clearance without prompting T cell exhaustion. The CAR T therapy worked against solid tumors. Encouragingly, some altered T cells also stuck around and became memory T cells. This is important because T cell exhaustion often prevents T cells from mounting a strong memory response to recurrent cancers.

Link: https://www.lji.org/news-events/news/post/preparing-t-cells-for-the-long-haul/

Cellular senescence occurs in response to stress, damage, and cells hitting the Hayflick limit on replication. Senescent cells cease replication, and begin to secrete a pro-inflammatory, pro-growth mix of signals. In cell cultures, senescence is a common phenomenon. Researchers are beginning to realize that the presence versus absence of senescent cells in culture may explain a sizable fraction of the variation in outcomes resulting from stem cell therapies. Slightly different methodologies of production of stem cells for transplantation may result in sizable differences in the proportion of those cells that are senescent, and thus the ability of the treatment to produce benefits to a patient.

Another consideration is the age of the donor. In today's open access paper, researchers demonstrate that mesenchymal stem cells taken from bone marrow are more senescent in culture and less capable of inducing regeneration following transplantation when the source is older mice versus younger mice. This problem can be mostly fixed by applying the senolytic combination of dasatinib and quercetin briefly to cultured cells, destroying many of the senescent cells, prior to transplantion. Senolytic treatment of cells to be used in cell therapies may well become commonplace in the years ahead.

Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice

Bone marrow mesenchymal stem cells (BMSCs) are a population of multipotent progenitor cells that have regenerative potential of various tissues. With aging, the function of BMSCs declines dramatically, and limited interventions exist to rejuvenate BMSC population from aged donors. The underlying mechanisms of age-related changes in BMSCs are not fully characterized. With aging, a portion of BMSCs might become senescent like other MSCs, and contribute to these changes. Cellular senescence refers to the stable arrest of cellular proliferation, and might impact aged BMSCs function by both intrinsic and extrinsic mechanisms.

Recently, various senolytic drugs have been developed to specifically kill senescent cells. The cocktail of dasatinib and quercetin (D + Q) is the first reported senolytic agents, and eliminates senescent cells by transiently suppressing senescence-associated anti-apoptotic pathways which are highly activated in senescent cells. In this study, an in vitro cell culture and in vivo transplantation model was used to assess the effect of D + Q on inherent osteogenic potential of BMSCs derived from old donors.

BMSCs cultures were established from young (3 month-old) and old (27 month-old) male mice, and were treated with vehicle (V) or D + Q for 24 hours. At the end of the 24 hour treatment period, an ATP-based assay revealed that D + Q-treated old BMSC cultures had 20-30% lower cell number than V-treated cells while the reduction of cell number in young BMSCs by D + Q was only 10%. These results indicate that D + Q has age-preferential killing effects on certain cell populations in BMSCs. The cultures were stained with senescence associated beta-galactosidase (SABG), a classic biomarker for cellular senescence in vitro. Old BMSCs contained more SABG + cells (20%) than young BMSCs (10%) and D + Q reduced SABG + cells in old (10%) but not young BMSCs.

The effect of D + Q on the bone forming potential of old BMSCs in vivo was assessed using the calvarial defect model. D + Q- or V-treated old BMSCs as well as young BMSC cultures were loaded into collagen-hydroxyapatite (HA) scaffolds and implanted into calvarial defects in 3-month-old immunodeficient mice. The area of newly formed mineralized tissue relative to the defect size was significantly lower in calvaria transplanted with V-treated old BMSCs (50%) compared to both young (90%) and D + Q-treated old cells (80%).

In summary, D + Q treatment improved the osteogenic capacity of old BMSCs, and resulted in bone organoids with restored bone remodeling and an enlarged and functional bone marrow space. D + Q does appear to be beneficial for restoring the bone and bone marrow forming potential of old BMSCs. These agents along with other senolytic compounds hold promise for improving BMSC function in aged populations.

A reliable, low-cost means of early detection of cancer would be of great benefit. Approaches to the treatment are advancing to the point at which very early stage cancer has a high rate of survival, and the side-effects of treatments for early stage cancer are becoming less onerous. In the ideal world, a yearly physical would include a low-cost cancer screen that robustly detects even small volumes of cancerous tissue. Various approaches are under development, such as those based on identification of signal molecules in the bloodstream. The alternative approach noted here, based on the use of engineered nanoparticles, is an interesting one, as it can in principle also be used to locate a cancer following the initial low cost screening.

Researchers have been developing cancer diagnostics that work by generating synthetic biomarkers that can be easily detected in the urine. Most cancer cells express enzymes called proteases, which help them escape their original locations by cutting through proteins of the extracellular matrix. Cancer-detecting nanoparticles are coated with peptides that are cleaved by these proteases. When these particles encounter a tumor, the peptides are cleaved and excreted in the urine, where they can be easily detected. In animal models of lung cancer, these biomarkers can detect the presence of tumors early on; however, they don't reveal the exact location of the tumor or whether the tumor has spread beyond its organ of origin.

Building on their previous efforts,researchers wanted to develop what they call a "multimodal" diagnostic, which can perform both molecular screening (detecting the urinary signal) and imaging, to tell them exactly where the original tumor and any metastases are located. To modify the particles so they could also be used for PET imaging, the researchers added a radioactive tracer. They also coated them with a peptide that is attracted to acidic environments, such as the microenvironment in tumors, to induce the particles to accumulate at tumor sites. Once they reach a tumor, these peptides insert themselves into cell membranes, creating a strong imaging signal above background noise.

The researchers tested the diagnostic particles in two mouse models of metastatic colon cancer, in which tumor cells travel to and grow in the liver or the lungs. After treatment with a chemotherapy drug commonly used to treat colon cancer, the researchers were able to use both the urine signal and the imaging agent to track how the tumors responded to treatment. This kind of diagnostic could be useful for evaluating how well patients respond to treatment, and for long-term monitoring of tumor recurrence or metastasis, especially for colon cancer. In the longer term, researchers hope that this technology could be used as part of a diagnostic workflow that could be given periodically to detect any kind of cancer.

Link: https://news.mit.edu/2021/cancer-test-nanoparticles-urine-0715

Stealth BioTherapeutics develops elamipretide, a mitochondrially targeted peptide that appears to improve mitochondrial function in older individuals. Mitochondria are the power plants of the cell, producing the chemical energy store molecule ATP to power cellular operations. Mitochondria falter with age, however, negatively affecting tissue function throughout the body.

Here, researchers note a short term gain in ATP production following elamipretide infusion. The results in detail make it clear that individual responses are highly variable, but the average settles down to a statistically significant 27% gain. Like other present approaches to improving mitochondrial function (e.g. various forms of NAD+ upregulation), demonstrating improved tissue function as a result of biochemical differences of this nature remains a challenge. Muscle function did not show compelling improvement in this study.

Loss of mitochondrial function contributes to fatigue, exercise intolerance, and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial.

Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions.

A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI.

These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

Link: https://doi.org/10.1371/journal.pone.0253849

Atherosclerosis, a condition in which fatty lesions form to narrow, weaken, and distort blood vessel walls, might be primarily thought of as a condition of macrophage dysfunction. The innate immune cells called macrophages are responsible for clearing out unwanted lipids from blood vessel walls. Unfortunately, the growing prevalence of oxidized lipids and an inflammatory environment arising in later life causes macrophages to falter at this task. Macrophages become inflammatory rather than helpful in the lesion environment, then are overwhelmed and die, but are still attracted in ever greater numbers to swell the size of the lesion.

Researchers have shown that some of these inflammatory and dysfunctional macrophages are senescent, and that removing them via the use of senolytic therapies helps to slow the progression of atherosclerosis in animal models. In today's open access paper, the role of senescent endothelial cells in blood vessel walls is considered. Senescent cells secrete inflammatory signals, so any population of senescent cells in the vicinity of an atherosclerotic lesion will make things worse by biasing macrophages towards adopting an inflammatory, unhelpful state, rather than working on repair of the lesion.

Given that, it is unclear as to which of the populations of senescent cell types in and around atherosclerotic lesions are most influential on the progression of the condition and growth of lesions, as present senolytic treatments will destroy all of them at the same time. It is a question that may not matter all that much at the end of the day, however. The practical road ahead is to produce senolytic therapies that can reliably and safely remove as high a proportion of senescent cells as possible from every tissue in the body.

Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis

A striking feature of cellular senescence is a stable cell cycle arrest, which prohibit the replication of damaged cells and consequently limit the tissue damage and resist tumorigenesis in the short-term. However, senescent cells become harmful in the long term, especially through secreting soluble factors including cytokines, chemokines, and matrix proteases, called senescence-associated secretory phenotype (SASP). Eliminating senescent cells prevents age-related organ dysfunction in the heart and kidney, and notably, expands the lifespan in mice. Also, senescent cell-depletion and senolytic agents that preferentially kill senescent cells improved physical function and showed beneficial effects in age-related diseases such as osteoarthritis and atherosclerosis. These findings strongly suggest the critical and causative role of cellular senescence in age-related diseases.

Senescence of vascular cells is involved in age-related vascular dysfunction including atherosclerosis. Senescent vascular cells have been detected in atherosclerotic plaque, and eliminating senescent cells prevented the progression of atherosclerosis. Also, crucial and causative roles of vascular smooth muscle cell senescence in atherosclerosis have been reported. However, a role of endothelial cell (EC) senescence in atherogenesis remains to be elusive, though potential role of senescent EC in atherosclerosis was reported. By utilizing endothelial progeroid mice, we identified EC senescence promotes atherosclerosis potentially through EC hyper-inflammability due to epigenetic alteration.

The authors of this paper argue for a greater use of more traditional measures of age-related frailty as the research community expands efforts to find biological biomarkers to measure the progression of aging. It is true that some groups have used weighted combinations of existing clinical tests, such as grip strength, walking speed, and so forth, to produce biomarkers of aging that are not that different in accuracy when compared to epigenetic clocks and the like. It seems likely that there is more room for long term improvement in terms of accuracy and utility on the biomarker side of the house, however.

Biological age is the concept of using biophysiological measures to more accurately determine an individual's age-related risk of adverse outcomes. Grading of the degree of frailty and measuring biomarkers are distinct methods of measuring biological age. Chronological age is rigid and fails to account for the variable effects of time on individuals. The construct of "biological age" aims to give a more ordered relation between an individual's current health state and their proximity to death. This in turn can enable a novel approach to individualizing care and potentially yield ways in which aging might be modified.

A quantitative approach to frailty yields a proxy measure of biological age that can be formulated from deficit accumulation indices and geriatric assessment. The great advantage of this approach is that it offers information that is immediately relevant to guiding treatment strategies and estimating prognosis. Biomarkers derived from the mechanistic underpinnings of aging hold out the promise of measuring processes of aging before clinically recognizable deficits ensue. So doing, they can complement the information about individuals' health that is required for appropriate care planning and that can readily be summarized in a frailty index. These clinically derived frailty indices can outperform measures of biological age in predicting proximity to death without incorporating chronological age into their measurement. Furthermore, the cost of routinely performing sophisticated biomarker-based measures of biological age is prohibitive.

Complementarity of biomarkers and frailty indices can be demonstrated through both measures used simultaneously or by being combined. Further, frailty indices can use biomarkers as deficits, even when normal ranges have not been established for that purpose. In ways like this, the siloed approach to biological biomarkers can be overcome, and perhaps enhanced, through their combination with frailty measures that are likely already to be in the clinical record or that can feasibly be derived from it.

Link: https://doi.org/10.1007/s11912-021-01097-9

There are many challenges inherent in trying to learn something about aging through analysis of the demographics of extreme human longevity. First of all, there are just not that many supercentenarians, making it very hard to obtain enough data to make statistically sound inferences about health, tied as it is to the many complex and varied processes of aging. Secondly, and as illustrated by the paper here, much of the data that might otherwise be useful is of poor quality due to issues of fraud and lax recordkeeping.

The concentration of remarkable-aged individuals, within geographic regions or 'blue zones' or within databases of people exceeding extreme age thresholds, has stimulated diverse efforts to understand factors driving survival patterns in these populations. Populations within remarkable-age databases and 'blue zone' regions have been subject to extensive analysis of lifestyle patterns, social connections, biomarkers, and genomic variants, under the assumption that these represent potential drivers behind the attainment of remarkable age.

However, alternative explanations for the distribution of remarkable age records appear to have been overlooked or downplayed. Previous work has noted the potential of bad data, population illiteracy or population heterogeneity to explain remarkable age patterns. More recent investigations revealed a potential role of errors, and potential operator biases in generating old-age survival patterns and data. In turn, these findings prompted a response with potentially disruptive implications: that, under such models, the majority if not all remarkable age records may be errors.

Here, we explore this possibility by linking civil registration rates and socioeconomic data to per-capita rates of remarkable age attainment, using data from every known centenarian (individuals aged 100 or over), semisupercentenarian (SSCs; aged 105 or over), and supercentenarian (aged 110 or over) from the USA, France, Japan, the United Kingdom, and Italy. These data reveal that remarkable age attainment is predicted by regional indicators of error and fraud including greater poverty, higher illiteracy, higher crime rates, worse population health, greater levels of material deprivation, shorter average lifespans, fewer old people, and the absence of birth certificates. In addition, French and Italian historical data indicate that supercentenarians are not likely to be born into longer-lived cohorts, but are born into undifferentiated or shorter-lived populations relative to their contemporary national averages.

Supercentenarian birthdates also exhibit 'age heaping' distributional patterns that are strongly indicative of manufactured birth data. Finally, fewer than 15% of exhaustively validated supercentenarians are associated with either a birth certificate or a death certificate, even in populations with over 95% death certificate coverage. As such, these findings suggest that extreme age data are largely a result of vital statistics errors and patterns of fraud, raising serious questions about the validity of an extensive body of research based on the remarkable reported ages of populations and individuals.

Link: https://doi.org/10.1101/704080

The accumulation of senescent cells with advancing age is harmful. Selectively destroying those cells, even as few as a third of them, and even just once in later life, produces significant benefits to health and life span in mice. Cells become senescent in response to molecular damage, or to the signaling of nearby senescent cells, or on reaching the Hayflick limit on cell replication, or in response to tissue injury. In youth, senescent cells are rapidly clearly by the immune system and programmed cell death, but in later life the balance of creation and destruction is tipped towards an ever-increasing number of such cells.

Senescent cells serve useful functions prior to running awry in old age. They help to coordinate regeneration and suppress the incidence cancer. They secrete signals that attract the attention of the immune system, spur growth, and provoke the short-term inflammation needed to resolve issues of damage in the body. Thus we might suspect that a blanket and continual removal of senescent cells could be harmful in some ways. In fact, mice do live longer when all senescent cells are continually removed, but that may only mean that the beneficial outcomes outweigh the negative outcomes, rather than there being no meaningful negative outcomes.

The present consensus is that periodic removal of senescent cells, which does produce rejuvenation and extend life span in mice, likely has no meaningful downside. It would clear out the problem lingering cells during short treatments, while at all other times allowing for the temporary formation of new senescent cells as needed, such as in response to injury. This consensus may or may not reflect reality, we shall see as ever more data accumulates. In today's open access paper, researchers hypothesize on the question of why senolytic treatments to clear senescent cells extend median life span to a greater degree than they extend maximum life span in mice. Does that outcome result due to harmful effects that arise in later life to counterbalance the benefits?

This seems a question that is hard to answer, involving the need for a much greater understanding of the relative contributions of different mechanisms of aging at different ages. It is quite possible that any one given mechanism of aging, such as cellular senescence, is more or less influential on mortality in middle age versus extreme old age. That may not require any great difference in the details of cellular senescence in an aging body, but rather arise because another mechanism becomes more important in late life, for reasons that have little to do with cellular senescence, outweighing gains due to a reduced burden of senescent cells. Without intervening in these other mechanisms, it is challenging to say anything about their importance. We only know that senescent cell clearance is exciting as a basis for rejuvenation because it was successfully attempted. Prior to that point, there was no good way to assign a relative importance to the role of cellular senescence in degenerative aging.

Senolytics and the compression of late-life mortality

Whilst work continues to explore the possible therapeutic benefits of senolysis, we recently suggested that it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence. Entry into the senescent state appears to be regulated, presenting questions about why such a response should have evolved. It seems a priori unlikely that a purely negative action would be favoured by natural selection. In terms of potential benefits, cellular senescence is often regarded as an anti-cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. Furthermore, other studies have shown that cellular senescence is beneficially involved in wound healing, development, and tissue repair.

We recently brought these findings and ideas together and concluded that evolutionary logic strongly supports the idea that the latter positive contributions are the main reason for the evolution of cellular senescence. We further suggested that, since the immune system appears to play a role in clearing senescent cells once they have performed their temporary functions, the observed age-related accumulations of senescent cells might arise simply because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).

The importance of understanding the role of senescent cells is further indicated by recent senolysis studies in mice, where it was found that treatment with senolytics resulted in a substantial increase in mean and median survival times. However, in each of the studies there was much less increase in the maximum survival time. Such an outcome is only possible if, following senolytic treatments, the deaths that are postponed to produce the increased mean / median lifespans become concentrated in the interval prior to the relatively unaltered maximum lifespan. Such a phenomenon constitutes a 'compression of mortality', which needs to be explained

We developed computer simulations of three possible mechanistic scenarios in order to gain a better understanding of possible modes of action of senolytic treatments. Scenario A, which supposes simply that senescent cells are all-important in ageing, was shown to be incompatible with experimental findings. Scenario B, which allows for other forms of damage to be involved and which also allows for senescent cells to drive these other forms of damage to some degree, was also found not to explain the data, although it does generate some interesting behaviours. In contrast, Scenario C proved to have the potential to explain the experimental findings. Scenario C includes the idea that the immune system plays an important role in removing senescent cells and related damage, but that this 'repair capacity' of the immune system is also negatively affected by senolytic drugs. In the case of a single senolytic treatment the repair capacity can recover, but if the treatment is given continuously (as in all the experimental studies), the repair capacity is chronically reduced. This leads to an accelerated accumulation of damage, causing a faster increase of mortality.

The future of cancer therapy, and ultimately an end to cancer, will be built atop mechanisms that are as close to universal as possible, such as inhibition of telomere lengthening, or that are relevant to a large fraction of cancers, such as the example noted here. Only broadly applicable mechanisms allow for the cost-effective development of therapies, treatments that can be proven in a few forms of cancers and then immediately deployed to treat many other forms of cancer. Biochemically, cancers are highly variable, even within the same type, and the cancer subtype by cancer subtype approach to medical development has been well demonstrated to move too slowly. Universal (or at least very broadly applicable) cancer therapies are in principle possible, and the development of the options presently on the table should be the primary focus of the field.

All cancers fall into just two categories, according to new research, based on the presence or absence of a protein called the Yes-associated protein, or YAP. YAP is either on or off, and each classification exhibits different drug sensitivities or resistance. YAP plays an important role in the formation of malignant tumours because it is an important regulator and effector of the Hippo signaling pathway. "Not only is YAP either off or on, but it has opposite pro- or anti-cancer effects in either context. Thus, YAPon cancers need YAP to grow and survive. In contrast, YAPoff cancers stop growing when we switch on YAP."

Many YAPoff cancers are highly lethal. In their new research, scientists show that some cancers like prostate and lung can jump from a YAPon state to a YAPoff state to resist therapeutics. When cancer cells are grown in a dish in a lab setting, they either float or stick down. The team of researchers found that YAP is the master regulator of a cell's buoyancy, where all the floating cells are YAPoff, and all the sticky cells are YAPon. Changes in adhesive behavior are well known to be associated with drug resistance, so their findings implicates YAP at the hub of this switch.

"The simple binary rule we uncovered may expose strategies to treat many cancer types that fall into either the YAPoff or YAPon superclasses. Moreover, since cancers jump states to evade therapy, having ways to treat either the YAPoff and YAPon state could become a general approach to stop this cancer from switching types to resist drug treatments."

Link: https://www.sinaihealth.ca/news/new-sinai-health-research-finds-common-denominator-linking-all-cancers/

Aging kills most people in the world, and near all people in the wealthier parts of the world. It doesn't just kill, but also produces decades of declining health and capabilities, increased pain and suffering. Addressing the causes of aging, uncovering the mechanisms of aging and treating them, should have been the top priority in medicine ever since the advent of modern antibiotics allowed for control over the majority of infectious disease. Decades in which meaningful progress could have taken place have been wasted, and work on the mechanisms of aging is still only a small field within the life sciences, a small industry within the biotech space. This must change. The advent of senolytic treatments to clear senescent cells shows that rejuvenation therapies are possible and plausible, and the SENS proposals - for senolytics and more - point the way to those therapies. What is the world waiting for?

The widespread improvement in global life expectancy at birth was one of the greatest achievements of the 20th Century. Today, most children born in high-income countries will live into their ninth decade, and possibly beyond. This represents a new reality for humanity. In 1816, for example, French children had a 1 in 4 chance of making it to 70 years; today life expectancy in France is higher than 4 in 5.

The fact that a child born today is more likely to live to old age makes ageing well a new health priority. In fact, it's a multi-trillion dollar target. Imagine a health intervention that improved health and lowered mortality at every age such that overall life expectancy increased by one year. We calculate that such an intervention would be worth a staggering $37 trillion in present value terms in the United States (US). That's the total value of healthier ageing to the US population - both current and future - at an annual rate of $725 billion. Our research also shows that whilst longer lives are valuable, the most valuable health priority of all is to ensure that healthspan rises to match lifespan; and that the period many spend in poor health towards the end of life is made as small as possible.

Because ageing is a cumulative phenomenon, ageing well is a lifelong process. This process can be supported by critical shifts in public health, better individual life and career choices, and healthier living conditions. It will also require the development of new treatments that aren't just aimed at specific age-related diseases but which target ageing itself. This isn't reflected in current funding practices. The US spends more than $4 trillion on healthcare annually but only $2.6 billion is allocated to the National Institute of Aging, which mostly focuses on dementia. Given the scientific progress being made in the field of ageing, and the scale of the future health challenge, more resources need to be invested.

The need for more funding is based on recent scientific developments. Scientists understand the biological mechanisms of ageing now more than ever and agree on the factors that contribute to it. Drugs that target these factors are already being developed in laboratories and biotech companies around the world. Research and treatments aimed at single diseases, such as cancer and dementia, are important. But a broader focus on delaying or even reversing ageing has considerable advantages. Firstly, given the number of age-related diseases, any successful treatment to reverse or delay ageing will aggregate benefits across multiple disease fronts. And secondly, treatments that delay ageing are highly beneficial because they lessen the probability of disease. Most children born in high-income countries today will grow to be old. As a global community, we must ensure that our response to an ageing population goes beyond supporting the elderly to ensuring that the current young become the healthiest ever future old.

Link: https://www.weforum.org/agenda/2021/07/all-s-well-that-ages-well-a-new-health-imperative/

Senescent cells accumulate in tissues throughout the body with age. The produce inflammatory sections that actively maintain a disrupted state of tissue maintenance, structure, and function. Targeted removal of senescent cells has produced rejuvenation in mice, reversal of measures of aging and the progression of numerous age-related conditions. One of the ways in which tissue is affected by senescent cells is the development of fibrosis, a malfunction of tissue maintenance that leads to the inappropriate deposition of scar-like structures and consequent loss of function. This occurs in numerous organs with age, notably the heart, kidneys, liver, and lungs.

One of the first conditions to show improvement as a result of treatments producing senescent cell clearance was idiopathic pulmonary fibrosis. Human trials have shown initially promising results, and are presently ongoing. In today's open access paper, the authors discuss in some detail the role of cellular senescence in the development of lung fibrosis, a pathology with no good, established treatment options at the present time. The prospect of a viable therapy for this and other forms of fibrosis based on targeted destruction of senescent cells is encouraging a great deal of interest and activity in the research community.

Cellular Senescence in Lung Fibrosis

Fibrosis and wound healing are essentially interwoven processes, driven by a cascade of injury, inflammation, fibroblast proliferation and migration, matrix deposition and remodelling. Pathological fibrogenesis that occurs in many diverse organs and diseases is a dynamic process involving complex interactions between epithelial cells, fibroblasts, immune cells (macrophages, T-cells), and/or endothelial injuries.

As a response to lung injury, many interrelated wound-healing pathways are activated in order to facilitate the repair, turnover, and adaptation of lung tissue. However, although their aetiology and causative mechanisms varies, the different fibrotic lung diseases all fail to properly eliminate inciting factors, leading to continued tissue damaging with an abnormal and exaggerated accumulation of extracellular matrix (ECM) components and collagen deposition. Another hallmark of lung fibrosis is that older individuals display impaired ability to restore tissue homeostasis, heal wounds and resolve fibrosis, resulting in tissue scarring and irreversible organ damage

The number of senescent cells gradually increases with age, and the presence of senescent cells is a common finding in age-related pathologies. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. Our understanding of the biology of senescence in an evolutionary context has led us to think about cellular senescence as an essential mechanism of antagonistic pleiotropy. This concept encompasses processes that are meant to be beneficial to the health of young organisms (as a strong tumour-suppressor mechanism, or integrating physiologically programmed mechanisms during development), but also can demonstrate deleterious effects in older organisms, most likely by promoting chronic inflammation and fibrosis that leads to both degenerative and hyper-plastic pathologies.

Antagonistic pleiotropy is key to understanding many aspects of lung fibrosis, especially the relationship between aging, cellular senescence, and lung fibrosis. In the lung, there is a relatively straightforward relationship to several environmental factors, such as tobacco smoke, air pollutants, environmental antigens, or infections, so the setting in which cellular senescence develops is fraught with dangerous stressors, including DNA damage and telomere attrition, oncogenic signalling activation, epigenomic stress, redox imbalance, or mitochondrial biogenesis dysfunction. This attribute might also explain the vulnerability of the lung to increases in senescence-inducing conditions that promote the loss of architectural integrity and elasticity, and subsequent pulmonary function impairment.

Many aspects of aging correlate with one another, only some of which are directly causally connected, rather than emerging from the same underlying cell and tissue damage that drives aging as a whole. We might expect dysfunction in the vascular system to contribute directly to neurodegeneration and loss of function in the brain. Stiffening of blood vessel walls causes hypertension, which in turn leads to a greater pace of rupture of capillaries throughout the body. Each of these events is individually insignificant, a very tiny stroke in effect, but this adds up over time. The more structural damage to the brain, the worse the outcome.

In recent years, through the growing investigations and the more in-depth understanding of aortic stiffness, it was found that aortic stiffness is not only related to increased risk of cardiovascular diseases and related mortality but also involved in the aging changes of brain and cognitive function. With advancing age, the aortic vessel wall's elastic fibers are gradually reduced and replaced by collagen fibers or deposition of calcification, which impairs aorta's elasticity and causes aortic stiffness. The stiffening and loss of recoil in the aorta would transmit excessive and damaging pulsatile load to the peripheral arteries of body organs. Theoretically, the brain is more susceptible to pulsatile damage due to its low-resistance and high-flow characteristics. Aortic stiffness was reported to be closely associated with cerebral structural changes, primarily the cerebral small vessel disease and brain atrophy. There have been studies that focus on the relationship between aortic stiffness and cognitive function. However, their results were inconsistent.

Among various pulse wave velocity (PWV) measurements for aortic stiffness, carotid-femoral PWV (cfPWV) that measure the PWV along the aortic and aortoiliac pathways is the recommended gold-standard non-invasive technique to assess aortic stiffness because of its reliability and feasibility, which is highly related with magnetic resonance imaging (MRI) directly measuring PWV. While brachial-ankle PWV (baPWV) or femorotibial PWV (ftPWV), the commonly used PWV index measured outside the main aortic track, reflects mainly the stiffness of the small arteries rather than pure aortic stiffness, its predicted value in cardiovascular disease is still controversial. Thus, considering the validation in clinic practice, we performed a systematic review and meta-analysis about the association between aortic stiffness measured using the validated aortic PWV and cognitive function, risk of cognitive impairment, or dementia to help clarify the association between aortic stiffness and cognitive function in the aging process.

Thirty-nine studies were included in the qualitative analysis, and 29 studies were included in the quantitative analysis. The aortic PWV was inversely associated with memory and processing speed in the cross-sectional analysis. In the longitudinal analysis, the high category of aortic PWV associated with a 44% increased risk of cognitive impairment compared with low PWV, and the risk of cognitive impairment increased 3.9% per 1 m/s increase in aortic PWV. Further, meta-regression analysis showed that age significantly increased the association between high aortic PWV and cognitive impairment risk.

Link: https://doi.org/10.3389/fnagi.2021.680205

This review paper, like many, is largely concerned with the layer of aging biochemistry that involves changes in gene expression and functional alterations in cell behavior that can be attributed to those changes. This is a downstream area of the biochemistry of aging, very complex, caused by simpler forms of underlying molecular damage. That damage should be the primary target for research and development, not the consequences of damage.

It is possible to produce compensatory therapies that attempt to force a reversal in the age-related change in expression of specific genes, but this will never be anywhere near as effective an approach as targeting the underlying causes. One root cause form of molecular damage will result in countless gene expression and functional changes. Every one of those changes is a major research project, in the way that most new medical technology is presently developed. It would be far better to go after the root causes, and thus address many downstream consequences with a single major research project.

Vascular aging is an independent risk factor for morbidity and mortality of age-related diseases, particularly cardiovascular diseases (CVDs) such as hypertension and atherosclerosis. Vascular aging is characterized by vascular stiffening, intimal and medial thickening, increased luminal diameter, reorganization of the extracellular matrix, and endothelial dysfunction. The theories for the mechanisms of vascular aging include inflammation, mitochondrial dysfunction, oxidative stress, telomere attrition, epigenetics, and autophagy.

Inflammaging occurs during physiological aging in the absence of an overt infection, which describes the low-grade, chronic systemic inflammation. Inflammaging plays a role in all age-related diseases such as CVDs, which affect the mortality and morbidity of elderly people. The activation of immune cells such as macrophages / monocytes and the endothelial cell dysfunction participates in vascular low-grade inflammatory processes.

Growing research has identified that hypoxia-inducible factor-1α (HIF-1α) has an important effect on the aging-related process, particularly regulating cardiovascular aging. Vascular endothelial growth factor (VEGF), which is regulated by HIF-1, is a significant regulator for angiogenesis and a vital player of vascular aging. The activity of HIF-1 decreases during aging and then downregulates the expression of VEGF and results in the impairment of angiogenesis. The research found that HIF-1α is involved in regulating vascular inflammation in macrophages by limiting excessive vascular remodeling. In conclusion, HIF-1α may be a potential therapeutic target in vascular diseases, particularly in vascular aging.

Link: https://doi.org/10.1002/agm2.12151

The Foresight Institute folk have been quite active over the course of a year of lockdown, running virtual gatherings and regular presentations, in which you'll find more than just the usual Bay Area communities of forward-looking individuals. The interests of the Foresight Institute principals include molecular nanotechnology, artificial general intelligence, and rejuvenation biotechnology, and so you will probably find at least a few of this year's salon presentations interesting.

The selection of events noted below are linked by the theme of biomarkers to measure the progression of degenerative aging. Aging is the consequence of accumulated cell and tissue damage, which progresses at different paces at different people. Variance in human pace of aging is near entirely a matter of lifestyle choices and degree of harmful environmental exposures, such as particulate air pollution or infectious pathogens. But measuring that variance in a useful way is much less interesting than being able to rapidly quantify the efficacy of potential age-slowing and age-reversing therapies.

Generally agreed upon measures of degenerative aging based on blood tests would greatly accelerate progress towards human rejuvenation, directing attention and funding towards better rather than worse approaches. At present, poor approaches can continue to thrive at the expensive of better approaches, given an environment in which there is little near-term reward for success nor accountability for failure in the matter of meaningfully changing the state of aging.

EpigeneticClocks: What's New and What's Missing? | Steve Horvath, UCLA

In this session, Steve Horvath, professor at the University of California Los Angeles, provided an overview of the current state of the epigenetic clock field and the new developments in it. Then he went on to talk about what is missing in regards to methylation clocks and the longevity field itself, as well as what might be the next steps - the holy grails we should strive to get to. He also went to address some of the common misconceptions tied to epigenetic clocks at the end.

Biomarker Standardization | Morgan Levine, Yale, Jamie Justice, Wake Forest School of Medicine

In this session, Morgan Levine, Assistant Professor at Yale, gave a sneak peek into the new epigenetic clock they are developing that is able to probe into multiple organ systems, as well as on a new approach how to calculate clocks that is much more reliable, enabling to generate insights from methylation clocks with much smaller samples required. The second talk was given by Jamie Justice, Assistant Professor at Wake Forest, that covered the current ways and strides the longevity field is making towards validating biomarkers of aging through clinical trials, shown on examples of a few senolytic trials they made. In the end she also explained how exactly the TAME trial, which she is a coordinator of, should serve as a vehicle for the field to move further and have a flagship trial to validate new aging biomarkers against in the future.

Biomarker and Aging Clock Development | Vadim Gladyshev, Harvard, Gordan Lauc, GlycanAge

In this session, Gordan Lauc (Genos Glyco and GlycanAge) and Vadim Gladyshev (Harvard), gave their point of view on biomarkers and aging clocks development. Gordan Lauc went through the interesting glycomic data they recently and insights it generated about aging and menopause, exceptional predictive capability of glycans for hypertension, and much more. Vadim Gladyshev then went through the approach to molecular signatures and biomarkers that they are employing to find and test interventions to extend lifespan. Part of it is also a new epigenetic clock called scAge functioning on a single cell basis. This clock enabled them to find when aging actually begins during embryonic development.

Mitochondrial uncoupling regulates heat production in cells by preventing energy produced by the electron transport chain from being directed to the production of adenosine triphosphate, an energy store molecule used to power cellular operations. Modestly increased uncoupling mimics some of the benefits of calorie restriction, meaning improved cell function, health, and life span. Greatly increased uncoupling is fatal, due to excessive heat production. Therein lies the challenge when it comes to the production of drugs that can induce mitochondrial uncoupling. Some progress has been made in recent years regarding strategies that lead to safe mitochondrial uncoupling drugs, and there are now a few drug candidates with published data in addition to the one described here.

Obesity, nonalcoholic fatty liver disease (NAFLD), and insulin resistance (IR) associated with visceral, hepatic, or ectopic fat are major risk factors for a number of chronic diseases including diabetes mellitus (DM), cardiovascular diseases, and cancer. These metabolic disorders are intrinsically involved in an energy imbalance between energy expenditure and calorie intake. An appropriate degree of calorie restriction (CR) ameliorates these disorders, and moreover, it is the only proven way to extend lifespan in mammals like rodents. It has already been shown in both primates and rodents that CR improves health, decreases age-related mortality, and extends lifespan.

The mitochondrial uncoupler 2,4-dinitrophenol (DNP) was widely used as a weight-loss agent in the 1930s; however, its use was accompanied by many severe adverse effects including hyperthermia, cataracts, agranulocytosis, and even death. These effects were ascribed to the narrow therapeutic window, and finally the FDA banned its use in 1938. Since then, the use of chemical mitochondrial uncouplers has been confined to their use as reagents for basic research. Nevertheless, there has been a revival in interest in their therapeutic applications, and attempts to discover safe chemical uncouplers have been made due to their energy-consuming benefit. In particular, liver-targeted mitochondrial uncoupling is a promising means of an efficacious and safe treatment for DM and hepatic steatosis.

Our initial screened compound cyanotriazole derivative 1 has a unique chemical structure different from any known mitochondrial uncouplers. We attempted to optimize it as a safe therapeutic option for metabolic disorders such as DM. In this optimization, we regarded safety as the most important factor; therefore, we primarily assessed organ distribution and the acute toxicity of the compounds as well as antidiabetic efficacy. We describe here the optimization process from initial screening hit compound to a liver-localized mitochondrial uncoupler OPC-163493, which recently demonstrated its potent antidiabetic and cardiovascular beneficial effects with acceptable safety.

Link: https://doi.org/10.1021/acsomega.1c01993

Targeted delivery of therapeutics remains one of the thorny issues in medical development. Everyone wants a way to deliver high doses of a therapeutic to a specific location in the body without it also ending up everywhere else. The major issue is that systemic administration will send the majority of whatever is injected into the body into the liver and lungs, and that limits the dose that can be applied to any other tissue. One approach is to conduct localized injections, but these remain a good option for internal organs only in cases of serious damage. For example, researchers here report on the adaptation of keyhole surgery techniques to the delivery of exosomes to the injured heart following a heart attack, in order to spur greater regeneration.

Scientists have explored using stem cell therapy as a way to regrow tissue after a heart attack. But introducing stem cells directly to the heart can be risky because they could trigger an immune response or grow uncontrollably, resulting in a tumor. Therefore, researchers have tried injecting exosomes - membrane-bound sacs containing proteins, lipids, and nucleic acids secreted by stem cells - into the heart, but they often break down before they can have therapeutic effects. Others have developed cardiac patches, or scaffolds that help implanted exosomes last longer, but they usually must be placed on the heart during open-chest surgery. Researchers wanted to develop an exosome solution that could be sprayed onto the heart through a tiny incision, avoiding major surgery.

The researchers mixed exosomes from mesenchymal stem cells with fibrinogen, a protein involved in blood clotting. They added this solution to a tiny, double-barreled syringe that contained a separate solution of another clotting protein called thrombin. When the team sprayed the solutions out of the syringe onto a rat's heart through a small chest incision, the liquids mixed and formed an exosome-containing gel that stuck to the heart. A mini-endoscope, inserted through a second small incision, guided the spray needle. In rats that had recently had a heart attack, the exosome spray lasted longer, healed injuries better and boosted the expression of beneficial proteins more than heart-injected exosomes. In pigs, the spray caused less severe immune reactions and surgical stress than open-chest surgery. The spray is a promising strategy to deliver therapeutic exosomes for heart repair.

Link https://www.eurekalert.org/pub_releases/2021-07/acs-nsc071421.php

Why is it that, when asked, people largely express the desire not to live much longer than the present human life span? Usually they want to do a little better than their peers, but no more than that. I have suggested that this is a matter of conformity and discounting of future value - that the value of expressing a conforming opinion now, or holding a conforming belief, wins out over the future value of more years of good health and life.

Another popular hypothesis is that most people believe that longer lives will be accompanied by more suffering, more dysfunction and disease, and thus they have no great appetite for it. This has sometimes been called the Tithonus error, after the mythic figure granted eternal life without eternal health. It is an erroneous belief because there is no practical way to achieve this outcome through progress in medical technology. One cannot keep a damaged machine running without addressing the damage, and one cannot keep an aged human alive without addressing aging. The only way to improve matters is to repair the underlying cell and tissue damage that causes aging, and thus improve function as well as life span.

The patient advocacy community has long tried to make it clear that effective therapies capable of extending human life span would also extend healthy life span, indeed must also extend healthy life span, rather than produce a longer and worse decline. To be effective, a therapy must slow or reverse the damage that causes aging, and that will inevitably produce a better state of health in later life in addition to a longer life. Advocates clearly still have a long way to go in delivering that message to the world at large, however.

Preferred life expectancy and the association with hypothetical adverse life scenarios among Norwegians aged 60+

How long older individuals prefer to live given hypothetical adverse changes in health and living conditions has been insufficiently studied. The current study addressed how long individuals want to live and under a set of adverse hypothetical life scenarios. The sample was a population of adults aged 60 years and above in Norway from the NORSE study. The results suggest a relatively high preferred life expectancy (PLE) compared to findings from other investigations, although comparisons across culture and context are inherently problematic.

The desire to live is considered a basic driving force, but high life expectancy may also be related to individual unfinished business aims, and tasks one would like to finish before dying. Older age translated into higher PLE, particularly among the very old respondents. In our study, there was a tendency for longer PLE among men compared to women, but the difference was not significant. Thus, we did not replicate findings from other studies reporting that women prefer somewhat shorter lives.

Adverse health and living conditions prevalent at older ages may reduce preference to live longer. This study investigated the relationship between six hypothetic situations and PLE: dementia, spousal death, becoming a burden, poverty, loneliness, or chronic pain. The finding that dementia had the strongest negative effect on PLE concurs with prior studies suggesting a widespread fear of dementia. Chronic pain was also strongly associated with lower PLE in this study. For many people, chronic pain has been found to reduce quality of life and limit opportunities for social activities. It is also noteworthy that the third-highest ranked reason for lower PLE in this study was the belief that one represents a burden. Perceiving oneself to be a burden can relate to other outcomes in terms of self-view, including a loss of dignity at older ages.

Slightly above half of the respondents stated that poverty would decrease how long they would like to live. Poverty increases the risk of lower quality of life, autonomy, and wellbeing at older ages and relates to a greater disease burden. Severe poverty is rare in Norway. Older age groups have experienced rapid decreases in poverty levels over the last decades. Nevertheless, the fear of poverty in old age can still be widespread among older individuals, many of whom have grown up in a context where poverty was more prevalent.

An area of intense interest in the academic and biotechnology communities is the development of cells that do not provoke an immune response due to mismatch of cell surface receptors. As a general rule, cells from one individual are rejected by any other individual. It is possible to minimize this outcome by eliminating MHC receptors, but there are other complex interactions between cell surface chemistry and portions of the immune system that can still act as a barrier to transplantation. A number of groups have developed approaches to address specific parts of this problem space, but no one winner has yet emerged. At the end of this road can be found universal induced pluripotent stem cells, enabling the generation of cells of any type, as needed. Those cells can then be used to grow tissues and organs, or in more traditional cell therapies, that are compatible with any patient, greatly reducing cost and logistical challenges.

The prospects of generating specialized cells in a dish that can be transplanted into patients to treat various diseases are encouraging. However, the immune system would immediately recognize cells that were recovered from another individual and would reject the cells. Hence, some scientists believe that custom cell therapeutics need to be generated from scratch using a blood sample from every individual patient as starting material. Researchers here followed a different approach, using gene editing to create 'universal stem cells' (named HIP cells) that are not recognized by the immune system and can be used to make "universal cell therapeutics."

The team tested the ability of these cells to treat three major diseases affecting different organ systems: peripheral artery disease; chronic obstructive pulmonary disease from alpha1-antitrypsin deficiency; and heart failure, increasingly a global epidemic with more than 5.7 million patients in the United States alone and some 870,000 new cases annually. The scientists transplanted specialized, immune-engineered HIP cells into mice with each of these conditions and were able to show that the cell therapeutics could alleviate peripheral artery disease in hindlimbs, prevent the development of lung disease in mice with alpha1-antitrypsin deficiency, and alleviate heart failure in mice after myocardial infarction.

One of the great benefits of this approach is that the strategy of immune engineering comes with a reasonable price tag. It would make the manufacturing of universal, high-quality cell therapeutics more cost effective, could allow future treatment of larger patient populations, and facilitate access for patients from underserved communities. "In order for a therapeutic to have a broad impact, it needs to be affordable. That's why we focus so much on immune-engineering and the development of universal cells. Once the costs come down, the access for all patients in need increases."

Link: https://www.ucsf.edu/news/2021/07/420961/engineered-cells-successfully-treat-cardiovascular-and-pulmonary-disease

Researchers are increasingly making use of machine learning approaches in order to produce measures of biological age, known as clocks, derived from weighted combinations of biological data: epigenetic status, protein levels, transcript levels, and so forth. In most such clocks, it is unclear as to how the underlying processes of aging act to produce the identified epigenetic marks or differences in protein levels. Researchers here build a protein-based clock that is restricted to immune system signaling molecules that are found in blood samples. Working backwards from the proteins identified as being important to the clock, they note one that can be suppressed to potentially reverse some of the inflammatory aspects of age-related immune dysfunction.

Researchers have created an inflammatory clock of aging (iAge) which measures inflammatory load and predicts multi-morbidity, frailty, immune health, cardiovascular aging and is also associated with exceptional longevity in centenarians. The study identified the soluble chemokine CXCL9 as the strongest contributor to iAge. It is a small immune protein that is usually called into action to attract lymphocytes to the site of an infection. "But in this case we showed that CXCL9 upregulates multiple genes implicated in inflammation and is involved in cellular senescence, vascular aging, and adverse cardiac remodeling. Silencing CXCL9 reversed loss of function in aging endothelial cells in both humans and mice."

Results from the initial analysis, which also included information from comprehensive clinical health assessments of 902 individuals, were validated in an independent cohort of centenarians and all-cause mortality in the Framingham Heart Study. According to the researchers, when it comes to health and longevity, the "age" of one's immune system most certainly trumps the chronological information that can be derived from a driver's license. "On average, centenarians have an immune age that is 40 years younger than what is considered 'normal' and we have one outlier, a super-healthy 105 year-old man who has the immune system of a 25 year old."

Study results involving cardiac health were also validated in a separate group of 97 extremely healthy adults (age 25 - 90 years of age). Researchers found a correlation between CXCL9 and results from pulse wave velocity testing, a measure of vascular stiffness. "These people are all healthy according to all available lab tests and clinical assessments, but by using iAge we were able to predict who is likely to suffer from left ventricular hypertrophy (an enlargement and thickening of the walls of the heart's main pumping chamber) and vascular dysfunction."

Link: https://www.buckinstitute.org/news/first-actionable-clock-that-predicts-immunological-health-and-chronic-diseases-of-aging/

A warning: we're going to be talking about the strange world of blockchains and cryptocurrency today, about which I am far less informed than is the case for matters relating to aging. Blockchains are a way to solve problems in distributed collaboration, allowing enforcement of transactions and outcomes without the need for a trusted third party. Implementations to date, most notably Bitcoin and Ethereum, have used the cost of large amounts of computation as the barrier that prevents cheating, but that requires a collectively equally large ongoing expenditure on computation on the part of participants in the network. That is an expense that people have been happy to undertake, as the rewards for participating outweigh the costs. Nonetheless, the community is now at the point at which the output of entire power stations goes towards fueling data centers dedicated to blockchains.

One of the trends underway in this strange world is an attempt to move away from the use of computational cost as an enforcement mechanism ("proof of work") to something based on provable ownership of tokens ("proof of stake"). This has turned out to be a technically difficult challenge and is an area of active research and development. One of the major blockchains, Ethereum, is on the verge of making that switch, but progress has been slow enough to allow one particular group to forge ahead with a plan to clone the Ethereum network with their own implementation of a proof of stake mechanism, calling the new project Pulse Chain.

The Pulse Chain principals believe they have finessed the legal side of things to allow for cloning a whole new blockchain and handing out tokens to everyone already on Ethereum without falling afoul of the SEC. Thus this looks a lot like easy funds, profit for nothing, to cryptocurrency insiders. Much (not all, but much) of the entrepreneurship that takes place within the cryptocurrency space can be viewed as some form of get rich quick scheme at the core, but there is a great deal of altruism along the way. Blockchain insiders donate their wealth to their favored charitable causes to a noteworthy degree, sometimes via the publicity events that have come to be called airdrops, a gift of tokens, after the old trope of helicopter money. There is a lot to unpack in that choice of name, regarding the views and sense of humor to be found in the blockchain community.

Which comes to the point of this post. The Pulse Chain principals are running an airdrop to gain publicity for the launch of their newly cloned blockchain. They, like many in that space, are in favor of the work of the SENS Research Foundation on the foundations of human rejuvenation. So, in a sizable act of charitable giving, they have connected donations to the SENS Research Foundation to the receipt of tokens on the Pulse Chain for the next ten days or so. In a few days at the end of last week, SENS Research Foundation received more than $20 million in donations, about four years of their present budget. That will make a big difference to the future of work on the foundations of rejuvenation biotechnology!

Why this much support for rejuvenation research now? The SENS Research Foundation has in the past few years received smaller, but still sizable donations of cryptocurrency from various noted figures in that community. This particular example is, I think, the strong support of a founder of a new blockchain, coupled to cryptocurrency insiders voting with their feet regarding their opinion on whether Pulse Chain will become a functional, valuable blockchain - i.e. will they see a rapid increase in the value of their tokens. They see profit in making a donation in order to access the Pulse Chain launch airdrop. There are other incentives under the hood, but that is about the long and the short of it. As is usually the case, one cannot look at this sort of thing without considering that we live in interesting times. The future is an odd place to be exploring, one day at a time.

The Pulse Chain Sacrifice Stage Has Started

Donations sent to the addresses at SENS.org/donate may be tax deductible for you. You must follow the SENS.org PulseChain instructions. Sacrifices to SENS.org during the sacrifice phase earn 25% less points compared to sacrifices at Pulse.info. SENS.org can also accept stocks and bank wires. Once the sacrifice phase is over, the total sacrifice points for each sacrificer's address's points (at the same metamask address) are totaled up across all the supported chains and the SENS.org report. This creates a list of sacrificers ranked by total points from largest to smallest. Everyone's sacrifice is publicly viewable during the period by checking the public balances of the sacrifice addresses list on each chain. This way you might know when you want to sacrifice some more to move up in the rankings.

SENS Research Foundation: Pulse Chain Airdrop Now Live

Please do not make your donation until you have read ALL of the instructions below and sent all of the required information.

You can donate to SENS Research Foundation in any currency, including any cryptocurrency that is traded at Coinbase (note that, in particular, this means we cannot accept HEX or XRP). Check our DONATE page for all the methods of donation that we accept at. There is no minimum donation threshold that must be met. If it's a cryptocurrency, it will have to be a coin that we accept - any coin that Coinbase trades - and our addresses are listed on our donation page cited above. To verify that your donation is yours, we are asking that you either send a source address (if it's a non-custodial wallet), or we'll give you a random number that your crypto donation must end in (if your wallet is on an exchange).

Once your donation is processed, we'll send you a confirmation email that will include your date of donation, its USD value, and your provided ETH wallet address within 48 hours of your donation. If this is correct, you have no further actions to take. If it is incorrect, you have 24 hours to correct any errors. After that, we will send that exact information to Richard Heart to finalize your entry into the Airdrop. Don't worry, the actual date of your donation is the date that will be sent to Richard Heart, regardless of when we get the information to him.

Raising animals in germ-free environments, including the absence of a gut microbiome, is a difficult and expensive undertaking, but it is known to slow the pace of aging in a variety of species, including mice. Researchers here work with flies, digging deeper into the mechanisms by which the absence of microbial species produces this outcome. At the high level we might take these studies to underscore the importance of the immune system in aging, and the degree to which it is negatively impacted by life-long interaction with various microbial species. That removal of pathogens is beneficial tells us something about the priority that should be placed on the development of means to restore and repair the aged immune system.

Commensal microbes provide a critical contribution to aging. Caenorhabditis elegans grown without a bacterial microbiome (axenic) live twice as long as those grown conventionally. Similarly, most analyses have suggested that Drosophila lifespan is extended by axenic growth, though that relationship depends on both growth conditions and the details of how such studies are performed. For example, lack of a microbiome, particularly early in life, may limit the development of a robust innate immune response and alter the expression of stress-response genes, and therefore sensitize an individual to later microbial challenge. Moreover, the presence of a microbiome can compensate for a diet with low protein content, perhaps because the bacteria themselves act as a food source. Multiple mechanisms, therefore, contribute to the modulation of lifespan in axenic conditions.

Additionally, some studies link the microbiome-dependence of lifespan to specific commensal species, or to the interaction of specific commensals with variants in the host genome or compounds in the environment. For example, in C. elegans, at least some of the linkage between the microbiome and aging seems to be mediated by specific microbially-secreted metabolites. Such specificity, however, is difficult to understand in light of the generality of the phenomenon, given the variety of species and experimental paradigms in which it has been observed.

Here, we perform genome-wide gene expression profiling of Drosophila raised either under conventional growth conditions or under axenic conditions. We find that approximately 70% of the systematic changes in gene expression that we observe with age under conventional conditions fail to happen when we grow the flies axenically. In essence, many of the typical correlates of Drosophila aging become uncoupled from the passage of time for the greater part of adulthood if the flies lack a bacterial microbiome.

Among the genes that do not show expected, time-dependent changes in expression when flies are raised axenically are those associated with two features of aging that are observed widely across animal evolution, a decline in the expression of stress-resistance genes and progressive activation of innate immunity, as well as others. Thus, while these processes are clearly critical regulators of organismal lifespan, our data suggest that they are separable from other aspects of the typical progression of age-associated changes in organismal gene expression. They seem, rather, to reflect a succession of strategies that the organism has evolved for different stages of its lifecycle in order to exist in a microbe-rich environment.

In contrast, genes associated with some age-correlated processes, including rhythmic behavior, maintenance of cuticular structure, olfaction, and a subset of metabolic and redox processes, show changes in level over time in the axenic state that are similar to those observed under conventional conditions, allowing us to use them as biomarkers to quantify the age-correlated physiological state of the germ-free animal. The experiments reported here, therefore, support the view that the organism is subject to a progression of separable processes that individually modulate organismal longevity, while also identifying biomarkers of a time-dependent, internal state of the animal that reflects its effective age.

Link: https://doi.org/10.1016/j.isci.2021.102703

If regular exercise were a drug, it would be prescribed for everyone - and particularly older people, given that the reductions in risk of mortality and many age-related conditions are sizable in comparison to what can be achieved via medical technology at the present time. Frailty and sarcopenia in particular are amenable to treatment via structured exercise programs: a perhaps surprisingly large degree of the loss of muscle mass and strength is a matter of disuse in later life, rather than the presently unavoidable damage of aging. Yet we live in a world in which near everyone in wealthier regions of the world exercises too little, and as a consequence suffers the declines of age more rapidly.

Physical function (i.e., aerobic capacity, gait speed, and muscle strength) has been proposed as a biomarker of healthy ageing, as it is predictive of adverse health events, disability, and mortality. The role of physical exercise as a therapeutic strategy for prevention of both disease and the associated decline in functional capacity has been emphasised repeatedly. Supervised exercise interventions in hospitalised older people (aged ≥75 years) have been proved to be safe and effective in preventing or attenuating functional and cognitive decline.

Unfortunately, few studies have explored the potential role of tailored physical activity guidelines to maximise exercise-related effect on function. Also, exercise has not been fully integrated into primary or geriatric medical practice and is almost absent from the core training of most medical doctors and other health-care providers. Physical trainers should be included in health-care systems to help manage physical exercise programmes for older patients.

Taking into consideration current evidence about the benefits of exercise for frail older adults, it is unethical not to prescribe physical exercise for such individuals. To promote healthy and dignified ageing, it is therefore essential to help health-care systems to more efficiently implement evidence-based exercise programmes for frail older adults in all community and care settings.

Link: https://doi.org/10.1016/S2666-7568(21)00079-9

As is discussed in today's open access paper, determining the risk of age-related disease is far from a solved problem. This is true even for cardiovascular disease, caused by degenerative processes that occur in every individual over the course of later life, and which would kill everyone in a world absent other fatal age-related conditions. Assessment of cardiovascular disease risk has received decades of sizable funding, large studies, and considerable attention from the research and medical communities. And yet it is still possible to write a lengthy paper on the very real shortcomings of present assessment approaches.

I believe that challenges in assessment of risk are a consequence of trying to assess risk based on factors that are only indirectly connected to causative processes. Aging is caused by forms of underlying molecular damage, and this damage creates a spreading network of downstream consequences, and further damage and problems caused by those consequences. A great deal of variability is present from individual to individual in this network, and so picking out parts of it may not be a good reflection of the actual burden of underlying, root cause damage. It would be better to assess that damage.

To take one example, senescent cell accumulation is an important contributing cause of aging. It isn't the only important contributing cause of aging, but it does appear to cause widespread dysfunction in tissues and systems throughout the body. Measuring senescent cell burden, once good non-invasive approaches are available to achieve this goal, should in principle be a better marker of disease risk than constructs based on lifestyle, diet, weight, and so forth. Once assays for cellular senescence exist, such as the blood sample microRNA approach under development by TAmiRNA, I'd imagine that we'll find out whether or not that is the case within a few years.

Cardiovascular risk and aging: the need for a more comprehensive understanding

The first half of the 20th century was marked by a shift in morbidity and mortality patterns in industrialized countries all over the world, moving from the leading role of infectious diseases to the increasing role of chronic, non-communicable diseases. In particular, cardiovascular disease (CVD) has been an important cause of morbidity and mortality, with coronary heart disease (CHD) being the leading cause of death. The primary reason for this transition was the discovery of antibiotics and vaccines, the widespread use of which has led to a decline in infectious diseases and increase in life expectancy and population aging.

CVD is a leading cause of morbidity and mortality worldwide, with the highest incidence and prevalence in an older population (> 60 years). Ever since the traditional CV risk factors were identified in the Framingham Heart Study, at the end of the 20th century, they have been used as the basis of risk-based strategies for predicting CVD and initiating drug therapy in primary CVD prevention. A number of predictive functions and score systems have been developed for CV risk assessment. Although there are some variations between the systems, most of them use the same limited set of variables, including age, sex, smoking, blood pressure, and cholesterol, to predict the ten-year absolute risk for developing CVD, or CVD-related death.

The current CV risk assessment systems have several limitations, which limit their implementation in practice and their efficacy in reducing the burden of CVD. Most systems perform well in the population from which they were derived but not in other populations. It is necessary to recalibrate the prediction equation for application in other populations, to allow for different CVD mortality rates and risk factor distributions. Another limitation is these systems' inability to represent the inter-individual variations in the CV risk accurately, so that a substantial proportion of individuals are wrongly classified, which can lead to either insufficient treatment or overtreatment. The variable age is the strongest CV predictor, and the current prediction models cannot distinguish between age and other risk factors.

Recent studies indicate that the effects of traditional CV risk factors attenuate among older individuals, and that other age-related factors, including comorbid conditions, become important for predicting CVD in older age. Based on the current knowledge, CVD develops concurrently with many comorbidities and other geriatric conditions, such as frailty, malnutrition, and sarcopenia, which share the common mechanisms and pathophysiology pathways as CVD. This is the reason why older people are very heterogeneous with respect to differences in their health status and functional performances, which makes CV risk prediction in older individuals complicated.

The interaction between senescent cells and macrophages is of great importance to wound healing. Differences in the behavior of these two cell types appear critical to proficient regeneration in species like salamanders versus poor regeneration and scarring in mammals. Fibrosis is a malfunction of tissue maintenance and regeneration, in which excessive scarring takes place, disrupting tissue function and structure. This too is connected to the presence and behavior of senescent cells and macrophages. In old individuals, there is a background of raised inflammatory signaling and a growth in lingering senescent cells. One way to look at fibrosis is that this chronic inflammation and persistence of senescent cells interferes in the normal signaling between transient senescent cells and macrophages in regeneration and tissue maintenance, leading to pathological outcomes.

Senescent cells are attractive candidates as drivers of age-related organ dysfunction. They are consistently seen in diseased and older tissues when compared with healthy age-matched controls, actively secreting pro-inflammatory and pro-fibrotic molecules capable of driving further (paracrine) senescence and propagating on-going tissue damage. This is potentially because they secrete pro-inflammatory cytokines in the senescence-associated secretory phenotype (SASP) which modify the surrounding environment.

Macrophages contribute to clearance of senescent cells by phagocytosis. This activity declines with age in multiple organ systems, including the kidney, as macrophages polarize from M1 to M2 in response to exogenous growth factors, and can potentially become 'senescent-associated' and possibly senescent themselves. This is followed by a concurrent increase in fibrosis with age, which negatively affects organ function.

New therapy strategies have been developed, both pharmaceutical and lifestyle changes that aim at reducing the burden of senescent cells and the SASP they generate, and reducing inflammation, aimed at removing blockades for macrophage polarity transitions essential for response to injuries. In this review, we examine senescent cells and the overlap between the direct biological impact of senescence and the indirect impact senescence has via its effects on other cell types, particularly the macrophage. The canonical roles of macrophages in cell clearance and in other physiological functions are discussed with reference to their functions in diseases of the kidney and other organs. We also explore the translational potential of different approaches based around the macrophage in future interventions to target senescent cells, with the goal of preventing or reversing pathologies driven or contributed to in part by senescent cell load in vivo.

Link: https://doi.org/10.3389/fimmu.2021.700790

The enormous reduction in cost and increase in capacity for analysis of living biochemistry over the past 20 years has led to vast warehouses of omics data: information on genomes, epigenomes, expression of transcripts and proteins, and more. Making something of this data in a reliable way is a more challenging proposition, and remains a work in progress. More data is almost always good in the long run, but the goal of science is understanding, not implementation. The data revolution in biotechnology may not greatly change the nature of the fastest path to human rejuvenation, which is to implement the SENS proposals for damage repair and see what happens. In the case of removing senescent cells, we can see that this produces rapid rejuvenation in mice, to a degree that is dramatic in comparison to any other approach to aging tested to date. If a tenth of the effort that goes into producing omics data went into furthering the SENS research agenda, we'd be much further along the road to radical life extension.

Biogerontologists are nowadays struggling with identifying actionable mechanisms of aging, with the goal of extending the time individual lives in good health, possibly delaying age-related diseases, and therefore reaching longevity. The issue is not simple to solve. In fact, although our understanding of aging biology in model systems has increased dramatically, thanks to the possibility to model the effect of single variants on the probability to extend our lifespan, Human aging and longevity are complex polygenic traits. They are influenced by the inheritance pattern of multiple genes/variants, each one with pleiotropic protective roles across several age-related diseases, and their interaction with environment. People can achieve older age while suffering major age-related diseases, because of their capability to survive those disorders, or they can escape entirely some of the most frequent causes of death and impairment, thus living not just a long but also a healthy life. The difference between these two aging trajectories and phenotypes is greatly discussed and investigated.

Biomedical innovation, and in particular research into "omics technologies," offers the promise of monitoring, preventing and treating age-related disabilities and diseases. Progress in genomics and functional genomics in the past decades have significantly supported our understanding of the molecular mechanisms associated with aging. However, it is nowadays clear that the complexity of aging requires a huge effort into data integration, building a broader omics profile, including genomics, proteomics, lipidomics or metabolomics, transcriptomics, etc.

Although the capacity to produce big data drastically increased over the years, integration, interpretation and sharing of high-throughput data remain major challenges. This seems even more challenging in the field of aging, because such an effort requires a more holistic view. Aging is not just the progressive decline of different functions, but rather a well-described phenotype, characterized by a complex remodeling across the whole organism. This is the key reason why omics technologies may greatly improve the definition of different aging phenotypes, and the classification of individuals with features ranging from the very frail, with a poor quality of aging, to the most extreme, the centenarian's phenotype, characterized by a long life.

Link: https://doi.org/10.3389/fgene.2021.689824

The SENS Research Foundation is hiring scientists! This is a chance to work at one of the hubs of the field of aging research, with a highly influential group of researchers and patient advocates. The SENS Research Foundation and its network of allies have played an important role in turning investigation of the mechanisms of aging from a toy field, in which intervention was never considered, into a serious field of translational research that has given rise to a growing biotech industry focused on slowing and reversing the processes of aging. In addition to advocacy, the SENS Research Foundation staff work to unblock slow-moving or underfunded areas of research that are nonetheless important to the development of future rejuvenation therapies.

The Strategies for Engineered Negligible Senescence (SENS) view of aging is a synthesis of the past century of data, focused on the accumulation of cell and tissue damage that arises as a result of the normal operation of a youthful metabolism. This is the root cause of aging, and periodic repair of this damage should be sufficient to produce meaningful rejuvenation. The first SENS position paper in 2002 included cellular senescence as a plausible contributing cause of aging and target for therapies, and today there are a dozen or more biotech companies working on senolytic therapies to clear senescent cells, while first generation senolytics have been shown to produce rejuvenation in mice, and are undergoing human trials for age-related conditions.

SENS Research Foundation Career Opportunities

Research Associate / Scientist - Boominathan Lab (MitoSENS)

The Boominathan lab at SENS Research Foundation is hiring highly motivated Research Scientists / Associates for a project geared toward translational therapies for mitochondrial dysfunctions. The successful candidate will use in vitro, in vivo, and stem cell models to address diseases due to mitochondrial DNA mutations. This research position is within a small but dynamic group that strives to develop a deep understanding and curative therapies using a gene therapy approach to treat mitochondrial myopathies.

Postdoctoral Research Fellow and Research Associate - Catabody Project

We seek a postdoctoral fellow to join our small but dynamic immunology team led by Dr. Amit Sharma. The project geared towards developing a novel way to remove abnormal tau aggregation. The project is potentially relevant for developing therapeutic mitigation of normal age-dependent cognitive decline, as well as for tauopathies like Alzheimer's disease and related disorders. This project involves utilizing enzymatic antibodies to target toxic tau aggregates. As part of the project we will explore ways of delivering antibodies into cells. We will use human induced pluripotent stem cell derived neuronal cells as a model system to test the catalytic antibodies and confirm tau degradation.

Postdoctoral Research Fellow and Research Associate - Senescence Immunology

We seek a postdoctoral fellow to join our small but dynamic immunology team led by Dr. Amit Sharma for a project geared toward investigating the mechanisms involved in the age-dependent decline in immune surveillance of senescent cells with the aim of finding promising interventions. There are three main projects currently for the postdoctoral fellow. One of the projects involves characterizing age-dependent phenotypes changes in the of Natural Killer cells and its implication on their ability to eliminate senescent cells in cell culture and mice models. The goal of the second project is to characterize the surface antigens on senescent cells and with the goal of developing CAR-NK cells with therapeutic application. The aim of the third project is to develop therapeutic interventions based on removal of these SASP proteins for enhancing immune surveillance of senescent cells.

Ferroptosis is a mode of programmed cell death that manages to be both fairly well explored in the broader research community and far less visible than other programmed cell death processes. It was first named and described about a decade ago, though of course researchers have long explored aspects of its biochemistry. There is some thought that ferroptosis may be connected to lysosomal dysfunction and accumulation of molecular waste in long-lived cells of the central nervous system, but in general it isn't much mentioned in the aging research field. This paper here provides an overview of why ferroptosis might be an interesting area of investigation, particularly in the context of neurodegenerative conditions.

Life is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs, and the whole body.

All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders. In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis, nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject.

In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.

Link: https://doi.org/10.1038/s41420-021-00553-6

Proteostasis describes the steady state of a cell, maintaining an appropriate balance of various forms of protein machinery in order to enable continued normal function. With advancing age, proteostasis becomes disrupted in numerous complicated ways. This is a downstream outcome of underlying molecular damage, the reactions to that damage, and immediate consequences of that damage. When a machine becomes worn and broken, it functions poorly. That is a simple thing to observe in a simple machine, but a cell is an enormously complex machine, and exhibits enormously complex dysfunctions as it departs from the proteostasis that is normal for youthful tissues.

The progressive decline in the buffering capacity of the proteostasis network represents one of the molecular hallmarks of aging. However, the biological reasons why the proteostasis network deteriorates during aging are complex and not well understood. A progressive decrease in the activity and efficacy of the protein quality control systems, as well as in the mechanisms mediating the functional cooperation between them, could be the cause of these dysfunctions.

A growing body of evidence indicates a complex and bidirectional association between protein quality control systems and inflammation. For example, Th1 or Th2 cytokines stimulated or inhibited autophagy, respectively. Also, TNF-α modulated proteasome and autophagy function in human skeletal muscle cells. LPS-induced neuroinflammation produced ER-stress and altered proteasome and autophagy activity. Also, unfolded protein response (UPR) activation has been found to increase the production of inflammatory cytokines. UPR components can activate the transcription factor NFκ-B, which has a pivotal role in the onset of inflammation.

Because aging is associated with a low grade of chronic inflammation, the modulation exerted by inflammation on cellular proteostasis might be particularly relevant in aged cells. For example, the immunoproteasome, which is not expressed in cells from young animals, is expressed in rat and human aged cells from several tissues. Moreover, proteasome turnover is regulated by neuroinflammation. Most of the age-related alterations observed in cellular proteostasis are often reproduced in young animals following LPS injection. For example, LPS induced the expression of the immunoproteasome and decreased proteasomal activity leading to the accumulation of polyubiquitinated proteins in pyramidal neurons.

This data collectively indicates that inflammation and proteostasis alteration should be considered as synergistic negative factors that might increase cell vulnerability in aging. This is especially relevant in the context of some age-related pathologies such as obesity, hypertension, diabetes, and neurodegenerative disorders, all of them characterized by oxidative stress and inflammation. However, having in mind the complexity in the reciprocal influences between inflammation and the different protein quality control systems, as well as the cell specificity of these interactions, further studies in the context of aging will be necessary to better understand the synergistic negative effects of these two processes.

Link: https://doi.org/10.3389/fmolb.2021.658742

Today's open access commentary is a good companion piece to a recent paper covering the use of mesenchymal stem cell therapies to suppress age-related chronic inflammation. These first generation stem cell therapies have proven to be unreliable when it comes to the original goal of regeneration of organ function, but they do reliably reduce excessive inflammation for some months. Transplanted stem cells near all fail to survive and engraft. Some clinics report better results than others on this front, but there is little understanding at present as to why similar cells sources and methodologies can produce wildly different outcomes in different hands. Benefits in most cases arise due to transient signaling by the transplanted cells that changes the behavior of native cells for some time.

The chronic inflammation of aging and physical frailty go hand in hand. Inflammation is disruptive of normal tissue maintenance, both of muscle tissue and in vital organs. Controlling inflammation can produce patient benefits. A great many clinical trials, including those aiming to treat age-related frailty, have been based on this approach of targeting regulatory mechanisms of inflammation. Still, first generation mesenchymal stem cell therapies are not yet as widely used as they might be, most likely due to the continued issues with consistency of outcomes from clinic to clinic and patient to patient. Much remains to be explored regarding the reasons why this variability exists.

Inflammation, a common mechanism in frailty and COVID19, and stem cells as a therapeutic approach

Many research labs have developed cell therapies in search for tissue homeostasis improvement. To date, there are more than 38 clinical trials using stem cells against the effect of aging or frailty, although there are far fewer with mesenchymal stem cells (MSCs). Recently, randomized double blind studies showed that intravenous administration of allogeneic MSCs is safe, renders improved physical performance, and reduces inflammatory markers increased in frailty states.

In the first of these trials, 15 patients with mild to moderate frailty were treated with MSCs. This phase 1 study focused on safety evaluating severe adverse effects during 12 months after the injection of 20 to 200 million MSCs. Besides safety, the results showed improvements in physical activity, cognitive hallmarks, and bloodstream TNF-α levels. In phase II (random, double blind with placebo), 30 frailty patients were injected with 100 to 200 million MSCs resulting in positive results in activity hallmarks and several immune biomarkers 6 months after the injection. These studies, together the other trials, support the safety and efficacy of the intravenous injection of allogeneic MSCs from bone marrow against frailty.

The downside of these studies is the lack of consistency among the methodology used, with significant variations in the number of infused cells, cell origin, quality of the donor and their MSCs, and hemocompatibility, all common problems of MSC therapies. Tolerance to these treatments, demonstrated in hundreds of patients in multicenter trials, and the reversion of some parameters compromised in frailty make these therapies a well-founded hope. However, to progress in this approach, the field will need the establishment of new and consistent animal models, as well as a better and systematized diagnosis of frailty conditions through more sensible and validated biomarkers.

In summary, MSC research during the last decades has been a rollercoaster of promises, controversies, and unexpected discoveries, which have changed our perspective of their potential use as a therapy on different human conditions and diseases. We believe that although the original promises have not been met, the intense dedication to their study has opened new alternatives to use their less known paracrine properties on immunomodulation and aging to find new solutions to extremely important challenges of public health, such as the increasing incidence of frailty conditions.

Atherosclerosis is an inflammatory condition. It is caused by dysfunction in the macrophage populations responsible for maintaining blood vessel walls, allowing fatty plaques to form, eventually leading to heart attack and stroke. This dysfunction is aggravated by a background of inflammatory signaling, and so there is some interest in finding ways to selectively interfere without preventing the beneficial activation of inflammation needed for normal immune function. That said, studies suggest that targeting inflammation in atherosclerosis is no more helpful than reductions in blood cholesterol, which is to say a modest reduction in mortality risk and only minimal reversal of existing lesions.

The protein CD40L is synthesized by, and expressed on the surface of specialized cells of the immune system. It is recognized by the CD40 protein, a membrane-bound receptor that is expressed on antigen-presenting cells. However, CD40L also binds to receptors on other cell types that have diverse physiological functions. Using a mouse model, researchers deleted the gene for CD40L specifically in T cells and platelets as well as its counterpart, CD40, on dendritic cells. They then crossed these mice with a strain that is particularly prone to develop atherosclerosis.

Secretion of interferon-gamma by T-cells is known to stimulate immune functions, but the CD40L-deficient T-cells were found to secrete less interferon-gamma than those in which the gene is intact. In addition, further experiments indeed showed that, in the absence of CD40L in T-cells, the atherosclerotic plaques that formed were smaller and more stable. This suggests that inhibition of CD40L could enhance the stability of atherosclerotic plaques, and thus reduce the incidence of heart attacks induced by the rupture of blood vessels.

Similar results were obtained in a mouse strain that was unable to produce CD40 in dendritic cells. Deletion of CD40L in platelets, on the other hand, had no effect on the incidence of atherosclerosis, but it was associated with a reduction in atherosclerosis-associated clot formation. Researchers are now extending their studies of the effects of CD40 und CD40L to other cell types, with the aim of developing drugs that can inhibit the functions of these proteins in a cell-specific fashion.

Link: https://www.lmu.de/en/newsroom/news-and-events/news/cardiovascular-disease-atherosclerosis-and-the-immune-system.html

This interview with a researcher working on the biochemistry of senescent cells notes the exploration of dihomo-γ-linoleic acid and derived compounds as potential senotherapeutics, capable of reducing the burden of senescent cells in old animals. At the end of the day there will be a very large number of such approaches, as the animal data for rejuvenation resulting from the clearance of senescent cells is impressive enough to drive a considerable growth in funding and interest. A sizable number of biotech companies are working on drugs to selectively destroy senescent cells, and many more programs are in earlier stages in academic labs.

There is a specific fatty acid made in small amounts in the body called dihomo-gamma-linoleic acid or DGLA. It's also present in tiny amounts in the diet. When I gave aged mice larger amounts of DGLA, they went from having quite a few senescent cells to having significantly fewer. This presents a new therapeutic target. I identified a candidate compound using the DGLA metabolic pathway that works at a dose that is over 1,000 times lower than fisetin, so you can imagine we're quite excited by these results.

Like many biomedical discoveries, it was accidental. DGLA makes anti-inflammatory lipids, which help alleviate conditions such as rheumatoid arthritis. I was studying this aspect of DGLA when I was surprised to discover that it killed senescent cells. My work is in its very early stages, and we've only studied a small number of mice, so it's too early for even tentative conclusions, although I'm obviously pleased that we've seen the elimination of a meaningful number of senescent cells in old mice. We'll be closely monitoring DGLA's positive effects as well as any negative effects on the mice.

First, we have to figure out how DGLA is killing senescent cells in mice. Again, not all studies with mice yield similar results in humans, so we are very careful about how we convey our findings and possible future actions. But I have met USDA researchers and nutrition scientists, and discovered that some of those folks were developing DGLA-enriched soybeans. In one scenario, you might go out for sushi and get a little bowl of DGLA-enriched edamame as a side. By the time you're done eating, you've helped reduce the odds of getting some age-related pathology. I don't know if it will play out that way, but it's an idea we're working toward. I also am working on therapies that elevate the amount of naturally occurring DGLA in senescent cells that I am very excited about, so this would be an alternative approach.

I am developing a quick and easy test to tell if senolytic therapy is working. Testing for senolytic effectiveness is not really being done now - you just look for improvement in symptoms or functioning and essentially conclude that it's due to the therapy. One way to solve this dilemma is to identify a biomarker, a measurable compound that consistently and reliably can confirm an intervention's effectiveness. For example, we know that a certain lipid, dihomo-15d-PGJ2, accumulates in large amounts inside of senescent cells. When we give a senolytic therapy that kills these cells in mice or human cells, this lipid is liberated. Detecting it in blood and urine is far less invasive, so that's what I'm working on now. Our aim is to be able to test people receiving senolytic therapy for the presence of dihomo-15d-PGJ2 in their blood and urine by the end of the summer.

Link: https://now.tufts.edu/articles/taking-harmful-cells-contribute-disease

The myriad ways in which the brain changes with age are in some ways very well explored, but overall still a dark forest, little understood in fine detail. One approach to gain greater understanding of the processes that cause declining cognitive function with age is to compare people with good function and people with poor function, first categorizing, and then secondly assessing the properties of the brain, as best researchers are able to do so, given limited access to the inside of the cranium. Today's research materials are an example of this sort of research, focused on trying to better understand why some older people retain a good memory function, while their peers decline.

There are numerous possibilities, even looking at broad categories of potential mechanisms. This could be a matter of slower degeneration, that some people make good lifestyle choices throughout life and as a result take longer to reach critical thresholds of damage and dysfunction that impact memory. One might look at recent research that suggests the hippocampus is running right at the upper limit of its supply of nutrients, and thus better maintained physical fitness into later life ensures that blood supply remains sufficient. Alternatively, some people may be more resilient to specific mechanisms of damage that impact areas of the brain, such as the hippocampus, that are important to memory. Some individuals have a high burden of amyloid-β in the brain, but little to no sign of neurodegeneration, for example.

Lastly, it is possible that some people exhibit a better set of age-related compensatory changes in the brain. This is perhaps driven by a greater pace of neurogenesis, allowing the creation of new neural networks and the replacement of damaged or dead neurons in existing networks. Neurogenesis in the hippocampus is meaningfully affected by exercise and gut microbiome, via mechanisms that include those related to expression of BDNF. The storage and processing of memories in the brain appears quite dynamic, and it is possible to envisage processes whereby memory is continually shuffled around and preserved through the loss of specific neurons or alternations to neural networks.

Study reveals source of remarkable memory of "superagers"

As we age, our brains typically undergo a slow process of atrophy, causing less robust communication between various brain regions, which leads to declining memory and other cognitive functions. But a rare group of older individuals called "superagers" have been shown to learn and recall novel information as well as a 25-year-old. The superagers are participants in an ongoing longitudinal study of aging. "Using MRI, we found that the structure of superagers' brains and the connectivity of their neural networks more closely resemble the brains of young adults; superagers had avoided the brain atrophy typically seen in older adults."

In the new study, the investigators gave 40 adults with a mean age of 67 a very challenging memory test while their brains were imaged using functional magnetic resonance imaging (fMRI), which, unlike typical MRI, shows the activity of different brain areas during tasks. Forty-one young adults (mean age of 25) also took the same memory test while their brains were imaged. While the participants were in the scanner, the researchers paid close attention to the visual cortex, which is the area of the brain that processes what you see and is particularly sensitive to aging.

In the visual cortex, there are populations of neurons that are selectively involved in processing different categories of images, such as faces, houses or scenes. During aging, this selectivity, called neural differentiation, diminishes and the group of neurons that once responded primarily to faces now activates for other images. The brain now has difficulty creating unique neural activation patterns for different types of images, which means it is making less distinctive mental representations of what the person is seeing. That's one reason older individuals have trouble remembering when they may have seen a television show, read an article, or eaten a specific meal.

But in the fMRI study, the superagers' memory performance was indistinguishable from the 25-year-olds', and their brains' visual cortex maintained youthful activity patterns. An important question that researchers still must answer is whether "superagers' brains were always more efficient than their peers, or whether, over time, they developed mechanisms to compensate for the decline of the aging brain.

Greater Neural Differentiation in the Ventral Visual Cortex Is Associated with Youthful Memory in Superaging

Superagers are older adults who maintain youthful memory despite advanced age. Previous studies showed that superagers exhibit greater structural and intrinsic functional brain integrity, which contribute to their youthful memory. However, no studies, to date, have examined brain activity as superagers learn and remember novel information. Here, we analyzed functional magnetic resonance imaging data collected from 41 young and 40 older adults while they performed a paired associate visual recognition memory task. Superaging was defined as youthful performance on the long delay free recall of the California Verbal Learning Test. We assessed the fidelity of neural representations as participants encoded and later retrieved a series of word stimuli paired with a face or a scene image.

Superagers, like young adults, exhibited more distinct neural representations in the fusiform gyrus and parahippocampal gyrus while viewing visual stimuli belonging to different categories (greater neural differentiation) and more similar category representations between encoding and retrieval (greater neural reinstatement), compared with typical older adults. Greater neural differentiation and reinstatement were associated with superior memory performance in all older adults. Given that the fidelity of cortical sensory processing depends on neural plasticity and is trainable, these mechanisms may be potential biomarkers for future interventions to promote successful aging.

Castration is known to extend life in male sheep. Researchers here show that epigenetic clocks constructed for this species show the expected slowing of epigenetic aging following castration. This is a way to dig deeper into the question of how it is that females live longer than males in mammalian species, an exploration of which mechanisms are important in determining that outcome. It is also a way to further explore how epigenetic clocks relate to biological aging. Since the clocks are constructed by machine learning approaches applied to epigenetic data, it remains far from clear as to what exactly they measure under the hood, meaning which of the processes of aging are driving changes in specific epigenetic marks used in the clocks.

In mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age and identifying novel factors influencing the aging rate using only DNA methylation data. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), which can predict chronological age with a median absolute error of 5.1 months. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens.

Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Comparable sex-specific methylation differences in MKLN1 also exist in bat skin and a range of mouse tissues that have high androgen receptor expression, indicating that it may drive androgen-dependent hypomethylation in divergent mammalian species. In characterizing these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.

Link: https://doi.org/10.7554/eLife.64932

Senescent cell behavior following injury is different and the clearance of these cells much more efficient in species like zebrafish and salamanders capable of regrowing organs. Researchers here suggest that senolytic therapies to selectively destroy senescent cells could be used in mammals to limit the scar formation that follows nerve injury, an important goal in enabling regrowth and restoration of nerve function. Their particular interest is spinal cord injury, their work should be applicable to the rest of the nervous system as well.

Mammals have a poor ability to recover after a spinal cord injury which can result in paralysis. A main reason for this is the formation of a complex scar associated with chronic inflammation that produces a cellular microenvironment that blocks tissue repair. Researchers have now shown that the administration of drugs that target specific cellular components of this scar can improve functional recovery after injury.

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

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

Link: https://www.eurekalert.org/pub_releases/2021-07/idmm-ch070121.php

The long years of failure to improve outcomes in Alzheimer's disease patients via the development of immunotherapies targeting amyloid-β has provoked a great deal of alternative theorizing and new exploration regarding the causes of the condition. The amyloid cascade hypothesis of the progression of Alzheimer's disease is being modified in numerous ways. In its original form, the formation of deposits of misfolded amyloid-β causes inflammation and other forms of disarray that sets the stage for later aggregation of tau into neurofibrillary tangles, which leads to the widespread death of neurons.

Some researchers believe that chronic inflammation, or persistent infection, or senescent cell accumulation, or all three, are in fact the primary drivers of the development of Alzheimer's, with amyloid-β aggregation as a side-effect. In this case, the amyloid-β stage of the amyloid cascade is replaced with one or more other mechanisms, with tau aggregation, neuroinflammation, and cell death remaining as the end stage of the condition. Other groups see the failing drainage of cerebrospinal fluid from the brain as a major contributing factor, allowing molecular waste such as aggregated amyloid-β to build up in the brain. Vascular dysfunction and consequent reductions in the supply of oxygen and nutrients to the brain is another contender as an important cause: outright vascular dementia does overlap significantly with Alzheimer's disease.

Here, researchers propose yet another modification to the amyloid cascade, which is that the real problem is a reduction in the levels of functional amyloid-β. Misfolding and aggregation of amyloid-β might be presumed to contribute to that issue, but given that some people exhibit both aggregates and sufficient functional amyloid-β, it seems more likely that other mechanisms are at work. It is worth remembering that amyloid-β is an antimicrobial peptide, a part of the innate immune defense against pathogens. The findings here may ultimately fit into models of Alzheimer's disease in which the disruptive influence of persistent infectious agents are an important driving factor.

Researchers question prevailing Alzheimer's theory with new discovery

Cognitive impairment could be due to a decline in soluble amyloid-beta peptide instead of the corresponding accumulation of amyloid plaques. To test this hypothesis, researchers analyzed the brain scans and spinal fluid from 600 individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative study, who all had amyloid plaques. From there, they compared the amount of plaques and levels of the peptide in the individuals with normal cognition to those with cognitive impairment. They found that, regardless of the amount of plaques in the brain, the individuals with high levels of the peptide were cognitively normal.

They also found that higher levels of soluble amyloid-beta peptide were associated with a larger hippocampus, the area of the brain most important for memory. According to the authors, as we age most people develop amyloid plagues, but few people develop dementia. In fact, by the age of 85, 60% of people will have these plagues, but only 10% develop dementia, they say. "The key discovery from our analysis is that Alzheimer's disease symptoms seem dependent on the depletion of the normal protein, which is in a soluble state, instead of when it aggregates into plaques."

High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis

This cross-sectional study of 598 amyloid-positive participants in the Alzheimer's Disease Neuroimaging Initiative cohort examined whether levels of soluble Aβ42 are higher in amyloid-positive normal cognition (NC) individuals compared to mild cognitive impairment (MCI) and Alzheimer's disease (AD) and whether this relationship applies to neuropsychological assessments and hippocampal volume measured within the same year.

Higher soluble Aβ42 levels were observed in NC (864.00 pg/ml) than in MCI (768.60 pg/ml) or AD (617.46 pg/ml), with the relationship between NC, MCI, and AD maintained across all amyloid tertiles. Each standard deviation increase in Aβ42 was associated with greater odds of NC than AD (adjusted odds ratio, 6.26) or MCI (1.42). Higher soluble Aβ42 levels were also associated with better neuropsychological function and larger hippocampal volume. Thus, normal cognition and hippocampal volume are associated with preservation of high soluble Aβ42 levels despite increasing brain amyloidosis.

The old guidelines for systolic blood pressure drew the line for increased risk of cardiovascular disease at 140 mmHg, with higher systolic blood pressure defined as hypertension. That dividing line was then moved down to 130 mmHg. In the past few years, further evidence has shown that elevated systolic blood pressure of 120 mmHg or above still produces increased risk, and that one shouldn't feel comfortable and safe in the 120-129 mmHg range. The risk of cardiovascular disease scales up with increasing blood pressure, and as noted here, also with the modern lifestyle choices leading to excess fat tissue, metabolic disease, and type 2 diabetes.

Blood pressure is written as two numbers. The first (systolic) number represents the pressure in blood vessels when the heart contracts or beats. The second (diastolic) number represents the pressure in the vessels when the heart rests between beats. Hypertension is diagnosed if, when it is measured on two different days, the systolic blood pressure (SBP) readings on both days is ≥140 mmHg and/or the diastolic blood pressure (DBP) readings on both days is ≥90 mmHg.

"The 2017 American College of Cardiology (ACC) / American Heart Association (AHA) BP guideline defined blood pressure ≥130/80 mm Hg as hypertension. This guideline showed that the normal level is less than 120/80 mm Hg and SBP 120-129 mm Hg and DBP < 80 mm Hg is elevated BP. However, little is known regarding whether elevated BP versus normal BP is specifically associated with a higher risk for coronary artery disease / cerebrovascular disease according to glucose tolerance status in real-world settings."

the authors addressed these research questions using a nationwide claims-based database that included information on 805,992 people enrolled with a health insurance provider for company employees and their dependents in Japan. In one arm of the study, they compared the cumulative incidence of coronary artery disease according to their SBP in individuals with normal, borderline, and elevated blood glucose, separately. The authors reported that, "a linear relationship was observed between cumulative incidence rates of coronary artery disease and SBP categories across all glucose tolerance status designations using SBP below 119 mmHg as the reference".

In another arm of the study, the investigators compared the cumulative incidence of cerebrovascular disease according to their SBP in individuals with normal, borderline, and elevated blood glucose, separately. Similarly, the authors observed a linear dose-response relationship between cumulative incidence rates of cerebrovascular disease and SBP categories across all glucose tolerance status. The study also found that combined together, the blood glucose status and blood pressure values had a synergistic effect on the incidence of coronary artery disease and cerebrovascular disease.

Link: https://www.niigata-u.ac.jp/en/news/7805/

Researchers have for some years proposed reprogramming of scar tissue cells in the injured heart as a way to produce a regrowth of healthy tissue, an outcome that does not normally occur. The heart is one of the least regenerative organs in mammals, and injury produces scarring and loss of function. A great deal of effort has gone towards the establishment of cell therapies to treat heart injuries, with some limited success, but reprogramming of native cells may prove to be a better option in the long term. As noted here, however, there is a great deal of work left to accomplish between the present state of the art and a future in which scar tissue in the heart can be safely reprogrammed into functional muscle.

The heart is composed of different types of cells, and cardiac function is carefully regulated, not only by cardiomyocytes, but also by other cells, such as vascular endothelial cells and fibroblasts. Cardiomyocytes account for approximately 30% of all cells in the heart, and at least 50% of the remaining cells are non-cardiomyocytes. Cardiomyocytes are terminally differentiated cells with no potential for self-renewal; cardiomyocytes that become necrotic due to myocardial infarction, heart failure, or other cardiac diseases are therefore replaced by proliferating fibroblasts. This situation results in scarring of the affected site due to the formation of fibrotic tissue. These fibrotic changes reduce the cardiac systolic function, and arrhythmia caused by scar tissue has a poor prognosis.

One promising approach to cardiac regeneration is to differentiate stem cells, such as induced pluripotent stem cells (iPS cells) into cardiomyocytes outside the body, and then transplant the differentiated cardiomyocytes into the body. However, generating the large numbers of cells required to replace as many as 1 billion cardiomyocytes lost to myocardial infarction or failing heart incurs enormous costs. It also poses other limitations, such as the presence of residual stem cells undergoing oncogenesis, and a low survival rate of transplanted cells

In 2010, we reported a novel strategy for the direct reprogramming of fibroblasts into cardiomyocytes. Based on these results, there are currently three possible pathways for the creation of cardiac muscle from fibroblasts. The three pathways can be summarized as follows: (1) full reprogramming of fibroblasts into iPS cells and subsequent cardiac differentiation, (2) partial reprogramming of fibroblasts into cardiac progenitor cells and subsequent differentiation, and (3) direct reprogramming of fibroblasts into cardiomyocytes. We proposed the concept of "direct cardiac reprogramming" in place of this conventional method of cell transplantation. This is a technique that converts cardiac fibroblasts, which are present in large numbers in the myocardium in cardiac direct reprogramming, into cardiomyocytes.

Three cardiogenic transcription factors: Gata4, Mef2c, and Tbx5 can induce direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs), in mice. However, in humans, additional factors, such as Mesp1 and Myocd, are required. Inflammation and immune responses hinder the reprogramming process in mice, and epigenetic modifiers such as TET1 are involved in direct cardiac reprogramming in humans. Direct cardiac reprogramming needs improvement if it is to be used in humans, and the molecular mechanisms involved remain largely elusive. Further advances in cardiac reprogramming research are needed to bring us closer to cardiac regenerative therapy.

Link: https://doi.org/10.1186/s41232-021-00168-5

The flexibility of skin, and other elastic tissue such as blood vessel walls, depends upon the structural arrangement of elastin in the extracellular matrix. Elastin is largely laid down during the developmental period of life, and not much repaired thereafter. Disruption of this structure is progressive over time, and is a major contribution to the changing physical properties and appearance of aging skin. The effects on blood vessels and other internal tissues are more important: loss of elasticity in blood vessels cascades to cause a great deal of downstream damage and dysfunction via its effects on blood pressure, on development of atherosclerosis, on supply of nutrients to tissues, and so forth.

Repair of elastin is a challenging problem. One cannot just add elastin to a tissue and hope for improvement, as the precise structure, amount, and interactions with other components of the extracellular matrix are all important. The only realistic approach is to guide cells into performing the same work of elastic depositition that occurred in early life. This is not a solved problem, as it is quite possible to trigger behavior that leads to unhelpful or even harmful elastin deposition, in which the structure and amounts are incorrect. Regulatory networks must be clearly identified and then manipulated in the right ways.

Some therapies tested over the past few decades do manage to create some improvement in measures of tissue elasticity, with good evidence for this improvement to involve elastin deposition. The use of minoxidil, for example, was originally introduced as a way to treat age-related hypertension. The side-effects at the necessary doses are significant and health-threatening, however, such as cardiac edema. A great deal of work remains to produce a viable elastic deposition approach that could be widely used.

Clinical Relevance of Elastin in the Structure and Function of Skin

Elastin is the main component of elastic fibers, which provide stretch, recoil, and elasticity to the skin. Normal levels of elastic fiber production, organization, and integration with other cutaneous extracellular matrix proteins, proteoglycans, and glycosaminoglycans are integral to maintaining healthy skin structure, function, and youthful appearance. Although elastin has very low turnover, its production decreases after individuals reach maturity and it is susceptible to damage from many factors. With advancing age and exposure to environmental insults, elastic fibers degrade. This degradation contributes to the loss of the skin's structural integrity; combined with subcutaneous fat loss, this results in looser, sagging skin, causing undesirable changes in appearance.

The most dramatic changes occur in chronically sun-exposed skin, which displays sharply altered amounts and arrangements of cutaneous elastic fibers, decreased fine elastic fibers in the superficial dermis connecting to the epidermis, and replacement of the normal collagen-rich superficial dermis with abnormal clumps of solar elastosis material. Disruption of elastic fiber networks also leads to undesirable characteristics in wound healing, and the worsening structure and appearance of scars and stretch marks. Identifying ways to replenish elastin and elastic fibers should improve the skin's appearance, texture, resiliency, and wound-healing capabilities. However, few therapies are capable of repairing elastic fibers or substantially reorganizing the elastin/microfibril network.

Current intrinsic treatment modalities, which stimulate or modulate endogenous elastin, typically involve cosmetics and topical skincare products. However, given the complexity of tropoelastin production, assembly, and crosslinking, there is limited evidence that topical skincare products can reach the dermal layers of the skin or sufficiently stimulate elastin production.

Successful extrinsic treatment modalities to replenish elastin may require delivery of structurally intact tropoelastin or elastin; most experimental strategies have utilized elastin fragments that are inappropriate for in vivo elastin assembly. Proposed therapies for the connective tissue disorder cutis laxa provide other potential targets for restoring elastin. For example, although no specific treatments for cutis laxa exist, it has been suggested that the disordered elastic fiber assembly in this disease might be corrected by supplementing certain carrier molecules that have a role in the secretory pathways for elastolytic enzymes involved in elastin production. Other potential therapeutic strategies for increasing elastin production include stimulation of elastin gene expression. However, because tropoelastin expression and elastin production are substantially reduced in adult tissues, even large increases in their expression are unlikely to be physiologically relevant.

Considering tropoelastin is the main component of elastin, a more viable approach to repairing elastic fiber networks may be to use recombinant human tropoelastin-based treatments. The recombinant human tropoelastin may act as a substrate for skin fibroblasts to promote collagen production and glycosaminoglycan deposition, contributing to tissue repair and improved hydration in skin. A recent study showed that surgical delivery of exogenous tropoelastin via a collagen-based dermal substitute leads to the development of an extensive elastic fiber network in the deep dermis. Recombinant human tropoelastin has demonstrated early promise for wound repair, scar prevention and treatment, cosmetic applications, and aesthetics; it can be used by skin cells as a substrate to produce new elastic fibers. The applied use of tropoelastin for these indications is therefore a promising area of study.

Klotho is one of the few well-established longevity-associated genes that works in both directions in animal models: less klotho shortens life span, while more klotho extends life. Klotho also improves cognitive function. The mechanisms by which klotho produces these outcomes remain poorly understood: there is the usual grab-bag of identified mechanisms, and little idea as to which are more or less important than the others, or as to whether the list is even near complete. In recent years, research results have indicated that klotho likely undertakes its important functions in the kidneys rather than the brain, and its effects are a reflection of the importance of kidney function to the body as a whole. Meanwhile, delivery of soluble α-klotho has been shown to be beneficial in mice, and some groups are presently in the early stages of developing this approach as a therapy for neurodegenerative conditions.

Cognitive dysfunction is a key symptom of ageing and neurodegenerative disorders, such as Alzheimer's disease (AD). Strategies to enhance cognition would impact the quality of life for a significant proportion of the ageing population. The α-klotho protein may protect against cognitive decline through multiple mechanisms: such as promoting optimal synaptic function via activation of N-methyl-d-aspartate (NMDA) receptor signalling; stimulating the antioxidant defence system; reducing inflammation; promoting autophagy and enhancing clearance of amyloid-β.

However, the molecular and cellular pathways by which α-klotho mediates these neuroprotective functions have yet to be fully elucidated. Key questions remain unanswered: which form of α-klotho (transmembrane, soluble, or secreted) mediates its cognitive enhancing properties; what is the neuronal receptor for α-klotho and which signalling pathways are activated by α-klotho in the brain to enhance cognition; how does peripherally administered α-klotho mediate neuroprotection; and what is the molecular basis for the beneficial effect of the VS polymorphism of α-klotho?

In this review, we summarise the recent research on neuronal α-klotho and discuss how the neuroprotective properties of α-klotho could be exploited to tackle age- and neurodegeneration-associated cognitive dysfunction.

Link: https://doi.org/10.1042/NS20200101

Recent research has suggested that the hippocampus, vital to memory function, has evolved to operate at the upper edge of its normal supply of nutrients and energy. Even minor reductions to that supply will produce functional issues in memory, and there are many mechanisms by which aging reduces the supply of nutrients and energy to the brain. Reduced blood flow is one important factor, due to loss of capillary density, vascular dysfunction, lack of fitness, heart failure, and so forth. The paper here is an interesting read in this context, looking at loss of efficiency in glucose metabolism in the aging hippocampus. The brain obtains most of its energy from processing of glucose, and disruption might be expected to produce negative consequences.

Aging is a process that adversely affects brain functions such as cognition. Brain activity is highly energy consuming, with glucose serving as the main energy source under normal circumstances. Whether the dynamics of glucose metabolism change with aging is not well understood. This study sought to investigate the activity-dependent changes in glucose metabolism of the mouse hippocampus during aging. In brief, after 1 hour of contextual exploration in an enriched environmental condition or 1 hour in a familiar home cage condition, metabolites were measured from the hippocampus of both young adult and aged mice with metabolomic profiling.

Compared to the home cage context, the enriched contextual exploration condition resulted in changes in the concentration of 11 glucose metabolism-related metabolites in the young adult hippocampus. In contrast, glucose metabolism-related metabolite changes were more apparent in the aged group altered by contextual exploration when compared to those in the home cage condition. Importantly, in the aged groups, several key metabolites involved in glycolysis, the TCA cycle, and ketone body metabolism accumulated, suggesting the less efficient metabolization of glucose-based energy resources. Altogether, the analyses revealed that in the aged mice altered by enriched contextual exploration, the glucose resource seems to be unable to provide enough energy for hippocampal function.

Link: https://doi.org/10.3389/fnagi.2021.700306

In today's research materials, scientists attempt to model future increases in maximum human longevity based on past data for supercentenarians, people aged 110 and older. This is an interesting exercise, but I think that all of the results have to be taken with a sizable grain of salt. Firstly, the data for extreme human outliers in longevity isn't great. A lot of it is of poor quality, and the portions that are well maintained do not include a sizable number of people. There are few survivors to such exceptional ages, which makes it hard to call any analysis of that data truly robust. This is a problem that afflicts all similar work on survival and longevity in the oldest individuals.

Secondly, and more importantly, extrapolating past trends in human longevity will tell us next to nothing about what will happen in the years ahead. Past trends in human life expectancy in late life are near entirely incidental, as none of the widely available approaches to treating age-related disease actually target the underlying causes of aging in any meaningful way. That is changing. There is now a longevity industry working on numerous forms of therapy that will slow or reverse the cell and tissue damage that causes aging. The use of senolytics to clear senescent cells will become widespread in the years to come. The old people of the 2030s will have a greatly reduced chronic inflammation and disruption of tissue function in comparison to those of today or past decades. That sort of night and day difference isn't accounted for by extrapolation of trends.

How long can a person live? The 21st century may see a record-breaker

The number of people who live past the age of 100 has been on the rise for decades, up to nearly half a million people worldwide. There are, however, far fewer "supercentenarians," people who live to age 110 or even longer. Such extreme longevity likely will continue to rise slowly by the end of this century, and estimates show that a lifespan of 125 years, or even 130 years, is possible. With ongoing research into aging, the prospects of future medical and scientific discoveries and the relatively small number of people to have verifiably reached age 110 or older, experts have debated the possible limits to what is referred to as the maximum reported age at death. While some scientists argue that disease and basic cell deterioration lead to a natural limit on human lifespan, others maintain there is no cap, as evidenced by record-breaking supercentenarians.

To calculate the probability of living past 110 - and to what age - researchers turned to the most recent iteration of the International Database on Longevity. That database tracks supercentenarians from 10 European countries, plus Canada, Japan and the United States. Using a Bayesian approach to estimate probability, the team created projections for the maximum reported age at death in all 13 countries from 2020 through 2100. Among their findings: there is near 100% probability that the current record of maximum reported age at death of 122 years will be broken; the probability remains strong of a person living longer, to 124 years old (99% probability) and even to 127 years old (68% probability); an even longer lifespan is possible but much less likely, with a 13% probability of someone living to age 130; it is "extremely unlikely" that someone would live to 135 in this century.

Probabilistic forecasting of maximum human lifespan by 2100 using Bayesian population projections

We use the exponential survival model for supercentenarians (people over age 110) but extend the forecasting window, quantify population uncertainty using Bayesian population projections, and incorporate the most recent data from the International Database on Longevity (IDL) to obtain unconditional estimates of the distribution of maximum reported age at death (MRAD) this century in a fully Bayesian analysis. Based on this analysis, there is a greater than 99% probability that the current MRAD of 122 will be broken by 2100. We estimate the probabilities that a person lives to at least age 126, 128, or 130 this century, as 89%, 44%, and 13%, respectively.

The paper here is a representative example of much of the mainstream of research into aging, in that it is focused on processes that are well downstream of the causes of aging. In effect they are mechanistic symptoms of aging, the taxonomy of disruptions to the normal operation of cells and tissues that is the result of the underlying processes of damage accumulation that drive aging. It is likely that focusing on downstream outcomes of aging will result in an expensive path to poor therapies, at least in comparison to a focus on the underlying causes of these outcomes. The results of damage are more complicated to understand and address than the damage itself. Further, preventing the outcomes of damage without actually trying to repair the damage itself is likely to be somewhere between hard and impossible to achieve.

Aging is the leading risk factor for several age-associated diseases such as neurodegenerative diseases. Understanding the biology of aging mechanisms is essential to the pursuit of brain health. In this regard, brain aging is defined by a gradual decrease in neurophysiological functions, impaired adaptive neuroplasticity, dysregulation of neuronal Ca2+ homeostasis, neuroinflammation, and oxidatively modified molecules and organelles.

Numerous pathways lead to brain aging, including increased oxidative stress, inflammation, disturbances in energy metabolism such as deregulated autophagy, mitochondrial dysfunction, and IGF-1, mTOR, ROS, AMPK, SIRTs, and p53 as central modulators of the metabolic control, connecting aging to the pathways, which lead to neurodegenerative disorders.

Also, calorie restriction (CR), physical exercise, and mental activities can extend lifespan and increase nervous system resistance to age-associated neurodegenerative diseases. The neuroprotective effect of CR involves increased protection against ROS generation, maintenance of cellular Ca2+ homeostasis, and inhibition of apoptosis. The recent evidence about the modem molecular and cellular methods in neurobiology to brain aging is exhibiting a significant potential in brain cells for adaptation to aging and resistance to neurodegenerative disorders.

Link: https://doi.org/10.1186/s12993-021-00179-9

It is well established that early embryonic development involves a process of rejuvenation. As much as possible of the molecular damage characteristic of adult cells is stripped away. The development of cellular reprogramming to produce induced pluripotent stem cells has provided researchers with additional insight into some of this mechanisms of this process of embryonic rejuvenation, such as the resetting of epigenetic patterns and restoration of mitochondrial function. Using epigenetic clocks to assess embryonic cells at various stages of development produces interesting results, as shown here.

Aging is characterized by a progressive accumulation of damage, leading to the loss of physiological integrity, impaired function, and increased vulnerability to death. While the aging process affects the entire organism, it is often discussed that the germ line does not age, because this lineage is immortal in the sense that the germ line has reproduced indefinitely since the beginning of life. This notion dates to the 19th century when August Weismann proposed the separation of the ageless germ line and aging body.

However, being in the metabolically active state for two decades or more before its contribution to the offspring, the human germ line accumulates molecular damage, such as modified long-lived proteins, epimutations, metabolic by-products, and other age-related deleterious changes. It was shown that sperm cells exhibit a distinct pattern of age-associated changes. Accordingly, it was recently proposed that germline cells may age and be rejuvenated in the offspring after conception. If this is the case, there must be a point (or period) of the lowest biological age (here, referred to as the ground zero) during the initial phases of embryogenesis. Here, we carried out a quantitative, data-driven test of this idea.

We developed a multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e., rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal aging.

Link: https://doi.org/10.1126/sciadv.abg6082

The accumulation of senescent cells is clearly an important contribution to the progression of degenerative aging. This was firmly established to be the case not by the careful examination of mechanisms, because it is very challenging to assign relative significance to the many different processes involved in aging, but rather by the selective removal of senescent cells in mice. The best way, and possibly the only practical way at the present time, to establish the relevance of a mechanism to aging and disease is to very selectively block just that mechanism and then observe the results.

In the case of senescent cell removal, the outcome is a rapid rejuvenation of many aspects of aging. Senescent cells clearly actively maintain a disrupted state of metabolism and tissue function via the signals that they secrete. Remove that signaling, and tissues begin to return to a more youthful function. This can produce quite profound reversals. In mice, for example, ventricular hypertrophy, the distortion and weakening of heart muscle, is reversed by treatment with therapies capable of removing senescent cells. That is a surprising result, and one that might make us all more optimistic as to the degree to which rejuvenation therapies will be able to help people in later life.

A great deal of effort is presently going into understanding the biochemistry of cellular senescence, particularly regarding how it arises, meaning the various contributing factors that tip the balance of cell fate towards senescence. Many researchers are interested in preventing senescence, which may or may not prove to be a better way forward than periodic selective destruction of senescent cells. At least some cells become senescent for a good reason, in that they are damaged in ways that can raise the risk of cancer. Further, approaches based on minimizing the onset of senescence in cell populations have yet to produce animal studies anywhere near as impressive as the rejuvenation that results from clearance of senescent cells. But time will tell.

Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Accumulating studies have proven the relationship between senescent cells and organismal ageing. Meanwhile, the concept of eliminating senescent cells to counteract ageing-related conditions has emerged and succeeded in rodent models. Researchers have found a large number of p16INK4a-positive senescent cells in various tissues that cause a range of ageing symptoms, including sarcopenia, cataracts, and lipodystrophy. Accordingly, targeted clearance of p16INK4a senescent cells alleviates the adverse symptoms and successfully extend the health span in many diseased models.

The field began to look for traces of senescent cells in common ageing diseases in humans, and successfully established a causal relationship between pathogenesis of ageing-related diseases and cell senescence. Take atherosclerosis as an example, we have known that plaques composed of fat and protein gradually accumulate on the inner arterial wall, which is prone to cause coronary atherosclerotic disease, stroke, or other ischemic severe diseases. Next, senescence-associated macrophages were recruited to the arterial wall, where the plaque initially formed. As time elapsed, other senescent cell types appeared near these sites. Compared with other control cells, these senescent cells expressed abundant secretory factors and metabolites that promoted the pathogenesis of atherosclerosis, concurrent with significant alterations in epigenetic imprints. Using a variety of approaches to remove these senescent cells attenuated the lesions, and thus alleviating the progress of atherosclerosis.

Consequently, focusing on the epigenetic and immunometabolic regulation of cell senescence may shed light on managing ageing-related diseases and therapeutic interventions. In this review, we highlight the recent advances in the understanding of the inflammatory, epigenetic, and metabolic basis of cell senescence, a comprehensive overview of relevant molecules and signaling pathways associated with cell senescence and organismal ageing are discussed. Finally, novel techniques and strategies intervening in the ageing process are briefly summarized.

Chimeric antigen receptor (CAR) technology was first applied to T cells of the adaptive immune system. A patient's T cells are extracted, engineered to express a surface feature that matches to the patient's cancer cells, expanded in culture, and introduced back into the body. This has proven to be highly effective against forms of leukemia. Researchers are attempting to apply this approach to other varieties of immune cell, and thus allow a greater range of efficacy against various classes of cancer. Here, researchers report on their efforts to engineer natural killer cells to recognize patient cancers.

Modified natural killer (NK) cells can differentiate between cancer cells and healthy cells. The experimental treatment is an alternative to chimeric antigen receptor T-cell therapy, or CAR-T. The engineered T-cells used in CAR-T therapy are highly effective against some blood-borne cancers but cannot distinguish between cancerous and non-cancerous cells. So while they offer important benefits, they are not uniformly applicable to all forms of cancer. In patients with solid tumors, the T-cells can cause devastating, even lethal side effects.

The team behind the research wanted a treatment with the same power as CAR-T, but which could be used safely against solid-tumor cancers. They first propagated natural killer cells taken from the blood of patients with breast cancer. Such cells perform a similar function to T-cells in the immune system. The researchers then genetically modified them to target specific receptors on cancer cells, successfully testing the CAR-NK cells in the laboratory on tumor cells derived from breast cancer patients

"The efficacy we see with CAR-NK cells in the laboratory is very promising and seeing that this technology is feasible is very important. Now, we have much better and safer options for solid tumors. These CAR-NK cells are a little bit smarter, in a way, in that they only kill the enemy cells and not good cells that happen to have the same marker. These engineered CAR-NK cells are an important step towards having a viable immunotherapy option in this large group of patients."

Link: https://brighterworld.mcmaster.ca/articles/natural-killers-researchers-engineer-cells-that-attack-and-destroy-malignant-tumor-cells-but-leave-the-rest-alone/

Researchers here suggest that reduced tryptophan intake can change the balance of populations in the gut microbiome to favor inflammatory microbes. Diet in late life is often deficient, with consequences that can approach outright malnutrition. It seems unlikely that this is a major issue earlier in life, however, and the gut microbiome exhibits harmful shifts in composition as early as the mid-30s. The influence of changes in the gut microbiome on health may be in a similar range to those of exercise, so it is a topic of growing interest in the research community. Ways to preserve or reset the gut microbiome have been demonstrated in animal studies, such as flagellin immunization or fecal microbiota transplantation. Bringing these and other approaches into human medicine should be a priority, given the comparatively low cost and risk.

With age, a diet lacking in the essential amino acid tryptophan - which has a key role in our mood, energy level and immune response - makes the gut microbiome less protective and increases inflammation body-wide, investigators report. In a normally reciprocal relationship that appears to go awry with age, sufficient tryptophan helps keep our microbiota healthy. A healthy microbiota in turn helps ensure that tryptophan mainly results in good things for us like producing the neurotransmitter serotonin, which reduces depression risk, and melatonin, which aids a good night's sleep.

But in aged mice, just eight weeks on a low-tryptophan diet results in some unhealthy changes in the trillions of bacteria that comprise the gut microbiota and higher levels of systemic inflammation. For example, when tryptophan levels are low, the investigators found lower levels of Clostridium, the bacterium that metabolizes the essential amino acid enabling production of good products like serotonin in the gut, and a threefold increase in the bacterium Acetatifactor, which is associated with intestinal inflammation.

The unhealthy changes they saw in the microbiota made researchers also suspect increased release of inflammation-promoting signaling molecules called cytokines, hypothesizing that microbiota changes might induce release of the molecules body-wide. They looked specifically at the largely inflammation-promoting IL-17 and IL-1a as well as IL-6 and IL-27, which can both promote and suppress inflammation, in the blood of mice on a low tryptophan diet. They found significant increases of IL-6, IL-17A and IL-1a and a significant decrease in IL-27, a cytokine which prevents transcription of inflammation-invoking IL-17 and helps do things like increase regulatory T cells in the gut, which suppress inflammation. Conversely, mice on a tryptophan-rich diet had higher levels of the calming IL-27.

When the aged mice resumed a healthy tryptophan intake, some of the unhealthy changes resolved in just a few days. But the reality that just increasing tryptophan did not always correct problems, and that some tryptophan metabolites are actually harmful, provides more evidence that a better option is giving select metabolites early on to help keep the microbiota functioning optimally, rather than attempting a tryptophan rescue.

Link: https://jagwire.augusta.edu/with-age-insufficient-tryptophan-in-the-diet-alters-the-gut-microbiota-increases-inflammation/

Atherosclerosis is characterized by the formation of fatty plaques in blood vessel walls, narrowing and weakening vessels. It leads to heart failure, as well as heart attack and stroke as the result of rupture of a blood vessel or plaque. Near all treatments for atherosclerosis are preventative, which is the better approach to medicine, and are focused on the outcome of lowering LDL cholesterol in the bloodstream, which is, unfortunately, not the better approach to atherosclerosis.

Atherosclerosis is, at root, a condition caused by macrophage dysfunction. Macrophages are the innate immune cells tasked with clearing debris from blood vessel walls. That debris includes errant cholesterol. Cholesterol is needed everywhere in the body, but is expensive to produce, and is only made in a few places, primarily the liver. Cells do not break down excess cholesterol, but rather traffic it around the body as needed via the bloodstream. Cholesterol made in the liver is attached to LDL particles and sent out into the body. Macrophages serve a vital function in returning excess cholesterol from blood vessel walls to the bloodstream, attaching it to HDL particles which return to the liver.

This complicated system works just fine in youth, but macrophages become dysfunctional with age, faltering in their task of cholesterol uptake and hand-off to HDL particles. This is thought to be largely an issue of rising levels of forms of oxidized and otherwise altered cholesterol, a consequence of oxidative stress and metabolic dysfunction in aged tissues. Macrophages are poorly equipped to process altered cholesterol, and become overwhelmed and inflammatory. Another contributing issue is a rising level of background inflammation, caused by immune system reactions to signs of age-related molecular damage in the body, among other causes. Macrophages can adopt different behaviors depending on their environment: the M2 phenotype is suitable for clearing out cholesterol from blood vessel walls, but inflammatory signaling provokes macrophages into the M1 phenotype instead.

The result is that atherosclerotic plaques become inflammatory hotspots of dysfunctional, dying macrophages. Their distressed signaling calls in more macrophages, forming a positive feedback loop that will proceed once established regardless of levels of LDL cholesterol in the bloodstream. Lowering LDL cholesterol takes some of the pressure off macrophages, and can result in a reduction of lipids in the worst plaques, but it has only a limited success in reducing mortality precisely because it doesn't reverse development of plaques to a meaningful degree. To do better than this, the macrophages must be rescued, made invulnerable (or at least more resilient) to the factors causing them to become dysfunctional. If macrophages in old tissues worked in the same was as they do in young tissues, there would be no atherosclerosis. Both Underdog Pharmaceuticals and Repair Biotechnologies are working on approaches to this goal.

A number of research groups also work towards improving macrophage function as an approach to the treatment of atherosclerosis, but not all such efforts are likely to be meaningfully effective. Metformin, for example, the subject of today's open access paper, influences some mechanisms of interest, such as those relating to inflammatory signaling. We know what the outcomes of metformin use on mortality are in humans, however, and they are certainly not good enough to justify a strong focus on this drug. Whether it can point the way to more effective treatments that target the same signaling mechanisms is an open question.

Metformin, Macrophage Dysfunction and Atherosclerosis

Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation, and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4, and HMGB1.

Macrophages, which are distributed in the circulation and tissues and aggregate under a variety of pathological conditions, can play an important role in a variety of diseases by regulating inflammation. Considerable evidence indicates that metformin can improve the dysfunction of macrophages which is a cause of atherosclerosis. We speculate that improving the function of macrophages may be the basis for the expanding therapeutic potential of metformin. Combined with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins, and IL-β inhibitor), this may help to further strengthen the pleiotropic actions and thus the therapeutic potential of metformin.

In addition, there is evidence that metformin can inhibit the formation of neutrophil extracellular traps (NETs), which may be related to the effect of metformin on improving macrophage function. In terms of research depth, single-cell sequencing helps to further clarify the mechanism of metformin and help to discover new targets for improving the function of macrophages and controlling or reducing the role of these cells in multiple disease processes and states.

There is good evidence for butyrate produced by the gut microbiome to increase neurogenesis via upregulation of BDNF. Here researchers show that indoles produced by gut microbes, via processing of tryptophan, also result in the outcome of increased neurogenesis. The balance of microbial species in the gut microbiome changes with age in ways that reduce this production of beneficial metabolites, as well as increasing the activity of harmful species that provoke the immune system into chronic inflammation. The combination of these issues may be as influential as physical activity on long-term health, judging from the benefits produced in animal models via transplantation of a youthful microbiome into old individuals.

The billions of microbes living in your gut could play a key role in supporting the formation of new nerve cells in the adult brain, with the potential to possibly prevent memory loss in old age and help to repair and renew nerve cells after injury. Researchers found that gut microbes that metabolise tryptophan - an essential amino acid - secrete small molecules called indoles, which stimulate the development of new brain cells in adults.

The team also demonstrated that the indole-mediated signals elicit key regulatory factors known to be important for the formation of new adult neurons in the hippocampus, an area of the brain also associated with memory and learning. Memory loss is a common sign of accelerated ageing and often an early sign of the Alzheimer's disease (AD).

"This finding is exciting because it provides a mechanistic explanation of how gut-brain communication is translated into brain cell renewal, through gut microbe produced molecules stimulating the formation of new nerve cells in the adult brain. These findings bring us closer to the possibility of novel treatment options to slow down memory loss, which is a common problem with ageing and neurodegenerative diseases. These include drugs to mimic the action of indoles to stimulate the production of new neurons in the hippocampus or to replace neurons damaged by stroke and spinal injury, as well as designing dietary intervention using food products enriched with indoles as a preventive measure to slow down ageing,"

Link: https://www.eurekalert.org/pub_releases/2021-06/s-gms062821.php

In the past researchers have found that a combined consideration of both duration and degree of being overweight is a better reflection of long-term health risks than a measure of weight made of any single point in time. This is reflective of underlying processes that cause lasting damage. Analogously, researchers here show that measuring the duration and degree of high blood pressure, hypertension, produces better correlations with cardiovascular disease risk than single measures at a point in time. Raised blood pressure causes structural damage to delicate tissues, leads to cardiac hypertrophy, accelerates the development of atherosclerosis, and raises the risk of a weakened blood vessel or atheroma rupturing to produce a heart attack or stroke. Some of this is a matter of lasting harm that will persist after blood pressure is reduced, at least in the context of today's medical technologies and capabilities.

Cumulative blood pressure (BP), a measure incorporating the level and duration of BP exposure, is associated with the risk of cardiovascular disease (CVD). However, the level at which cumulative BP could significantly increase the risk remains unclear. This study aimed to investigate the association of 15-year cumulative BP levels with the long-term risk of CVD, and to examine whether the association is independent of BP levels at one examination.

Data from a 26-year follow-up of the Chinese Multi-provincial Cohort Study-Beijing Project were analyzed. Cumulative BP levels between 1992 and 2007 were calculated among 2429 participants free of CVD in 2007. Cardiovascular events (including coronary heart disease and stroke) occurring from 2007 to 2018 were registered. Adjusted hazard ratios (HRs) for CVD incidence associated with quartiles of cumulative systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated.

Of the 2429 participants, 42.9% (1042) were men, and the mean age in 2007 was 62.1 ± 7.9 years. Totally, 207 CVD events occurred during the follow-up from 2007 to 2018. Participants with higher levels of cumulative SBP or DBP exhibited a higher incidence rate of CVD. Compared with the lowest quartile of cumulative SBP, the HR for CVD was 1.03, 1.69, and 2.20 for the second to the fourth quartile of cumulative SBP, and 1.46, 1.99, and 2.08 for the second to the fourth quartile of cumulative DBP, respectively.

In conclusion, our study demonstrated that elevated cumulative SBP or DBP was independently associated with increased risk of CVD in the Chinese population. Among participants with 15-year cumulative BP levels higher than the median, that is, 1970.8/1239.9 mmHg-year for cumulative SBP/DBP, which was equivalent to maintaining SBP/DBP level higher than 131/83 mmHg in 15 years, the CVD risk would increase significantly irrespective of whether or not the BP measurements at one examination was high. Our findings emphasize the importance of cumulative BP level in identifying individuals with high risk of CVD in the future.

Link: https://doi.org/10.1097/CM9.0000000000001383

Upregulation of telomerase expression and, separately, follistatin expression have been shown to extend life in mice. In recent news, researchers report a novel approach to delivering these two genes via gene therapy, making use of cytomegalovirus (CMV) as a vector. CMV is actually a major threat to human health, and might be responsible for a great deal of the age-related decline of the immune system. Near everyone is infected by the time old age rolls around. Nonetheless, one can develop viral vectors in which replication (and thus any threat of infection) is disabled, and these are widely used as tools in research and development.

Cytomegalovirus is most analogous to adeno-associated virus (AAV) in terms of how it works to make a cell produce desired proteins without introducing new DNA into the genome. It appears to be good at delivering its cargo to immune cells in particular, which may go some way towards explaining positive outcomes for telomerase in the study noted below. Immune system function is very important in aging, and immune cells replicate dramatically in response to infection. An increased capacity to replicate may do more good in the immune system than anywhere else in the body.

Telomerase upregulation extends life via a general boost to cell function, and probably stem cell function in particular. Telomerase acts to extend telomeres, which shorten with each cell division, enabling cells to push back the Hayflick limit in order to replicate and work for longer. In mice at least, the risk of cancer due to damaged cells remaining active appears more than compensated for by improved function in the immune system or other anti-cancer mechanisms. Cancer is reduced, but exactly why this is the case is still poorly explored. It is also possible that telomerase has meaningful effects on mitochondrial health in old age via its less well explored functions in the cell. No protein has just one task in the body; evolution likes reuse.

Follistatin is an inhibitor of myostatin, which in turn suppresses muscle growth. The effect of follistatin upregulation is thus a sizable growth in muscle mass, though it also reduces inflammation, fat tissue mass, and infiltration of fat into muscle tissue, among other beneficial shifts in metabolism. Mice engineered to overexpress follistatin or lacking myostatin are very heavily muscled, and as shown in the research here, live longer than their unmodified peers.

New intranasal and injectable gene therapy for healthy life extension

How to achieve healthy longevity has remained a challenging subject in biomedical science. It has been well established that aging is associated with a reduction in telomere repeat elements at the ends of chromosomes, which in part results from insufficient telomerase activity. Importantly, the biological functions of the telomerase complex rely on telomerase reverse transcriptase (TERT). TERT plays a major role in telomerase activation, and telomerase lengthens the telomere DNA. Because telomerase supports cell proliferation and division by reducing the erosion of chromosomal ends in mitotic cells, animals deficient in TERT have shorter telomeres and shorter life spans. Recent studies on animal models have shown the therapeutic efficacy of TERT in increasing healthy longevity and reversing the aging process.

The follistatin (FST) gene encodes a monomeric secretory protein that is expressed in nearly all mammalian tissues. In muscle cells, FST functions as a negative regulator of myostatin, a myogenesis inhibitory signal protein. FST overexpression is known to increase skeletal muscle mass in transgenic mice by 194% to 327% by neutralizing the effects of various TGF-β ligands involved in muscle fiber break-down, including myostatin and activin inhibition complex. These findings strongly implicate the therapeutic potential of FST in the treatment of muscular dystrophy and muscle loss caused by aging or microgravity. Thus, TERT and FST are among prime candidates for gene therapy aimed to improve healthy life spans.

As more longevity-supporting factors are discovered, it is of interest to determine potential large capacity vectors for delivering multiple genes simultaneously. Unlike AAV, lentiviruses, or other viral vectors used for gene delivery, cytomegaloviruses have a large genome size and unique ability to incorporate multiple genes. Cytomegaloviruses also do not integrate their DNA into the host genome during the infection cycle, thus mitigating the risk of insertional mutagenesis. They also do not elicit symptomatic immune reactions in most healthy hosts. Notably, the CMV vector does not invoke genome instability and has not been identified to cause malignancies. Human CMV (HCMV) has been proven a safe delivery vector for expressing therapeutic proteins in human clinical trials.

Using mouse cytomegalovirus (MCMV) as a viral vector, we examined the therapeutic potential of TERT and FST gene therapy to offset biological aging in a mouse model. We found that the mouse cytomegalovirus (MCMV) carrying exogenous TERT or FST extended median lifespan by 41.4% and 32.5%, respectively. This is the first report of CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity. Treatment significantly improved glucose tolerance, physical performance, and prevented loss of body mass and alopecia. Telomere shortening seen with aging was ameliorated by TERT, and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects. Translating this research to humans could have significant benefits associated with increased health span.

There is an increasing focus in the research community on the role of chronic inflammation in the development of Alzheimer's disease. With age, the background level of inflammatory signaling rises as the immune system constantly responds to signs of damage and dysfunction. Immune cells become overactive. In the case of the innate immune cells known as monocytes, that give rise to macrophages, an inflammatory background shifts their focus away from supporting processes of regeneration and tissue maintenance, and into a more aggressive and inflammatory state. This has detrimental effects on long-term health, and contributes to the onset of many different age-related conditions.

Alzheimer's disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes and macrophages is still largely unknown, especially concerning their role in the various stages of AD.

AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. To further investigate the roles of monocytes and macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI, and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease.

We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Thus our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients.

Link: https://doi.org/10.1186/s12979-021-00236-x

The accumulation of senescent cells is an important cause of degenerative aging. These cells secrete a mix of signals that produces chronic inflammation and disrupts tissue maintenance and function. Researchers here note that oxidative stress and oxidative signaling appear to be important in cellular senescence. These aspects of cellular metabolism are influenced by many of the small molecule drugs that have been found to affect senescence, either by slowing the pace at which cells become senescent, or by selectively inducing apoptosis in senescent cells.

Myriad stress stimuli trigger the acquisition of senescence and/or its maintenance, which in addition to promoting tissue repair and remodeling also functions as an effector mechanism driving age-related pathologies. The functional dichotomy of senescence is visibly manifested in regulating signaling networks that suppress or promote the process of carcinogenesis and its progression. These biological responses are a function of the slew of cytokines and chemokines secreted by cells upon acquiring the senescence-associated secretory phenotype (SASP). Despite the current advancement in the understanding of various stimuli and signaling networks upstream and downstream of SASP, there is relative lack of clarity with respect to the temporo-spatial factors/events that govern the switch from the good (onco-suppressor) to the bad (oncogenic).

Importantly, the intricate crosstalk between senescence and cellular redox metabolism has potential therapeutic implications. To that end, it's worth pointing out that a majority of small molecule compounds with senomorphic and/or senolytic activities also elicit redox regulatory effects. The challenge obviously would be to untangle the inherent complexity of the redox-senescence interplay, which will inform the appropriate clinical utility of these strategies as well as selective repurposing of other drugs.

Could regulation of cellular redox status be the common denominator in senolytic and senomorphic strategies? In this regard, aside from the deleterious effects on bio-molecules, aberrant redox signaling, downstream of DNA damage response activation, could be critical in the maintenance of senescence, and as such restoring redox homeostasis could have the dual advantage of blocking the acquisition as well as maintenance of the senescent phenotype. Hence, one might dare to conjecture that, in addition to accumulating oxidant-mediated damage over time, ageing involves a further role for an aberrant redox microenvironment in promoting cellular senescence.

Link: https://doi.org/10.1016/j.redox.2021.102032

An impressive regenerative capacity often goes hand in hand with longevity. Salamanders are capable of regrowth of lost limbs and injured internal organs, and are unusually long-lived for their size. Like other smaller species that exhibit an exceptional life span, salamanders are the subject of research initiatives that aim to find the relevant biochemical differences that produce greater species longevity. Additionally, scientists are very interested in understanding the specific mechanistic differences between mammals, largely incapable of regeneration without scarring, and species such as salamanders that are capable of scarless regeneration.

More inroads have been made into the question of regeneration than the question of longevity, and it remains far too early to say whether or not there is anything in salamander biochemistry that can be adapted into therapies and safely applied to a mammal in order to lengthen life span. The genetics and cellular metabolism that underlies differences in species life span is a complex swamp of detail piled upon detail, poorly understood and poorly mapped. Progress is slow, as there are only so many researchers in this part of the field, and only so much funding.

Salamander Insights Into Ageing and Rejuvenation

A salient feature of salamander regeneration is its resilience. Urodele regenerative capacity does not decline with time, and most studies suggest it is not impaired by repetitive regeneration events. A landmark study tracked the process of lens regeneration over 16 years in Japanese newts, removing the lens from the same animals 18 times and allowing them to undergo regeneration. Remarkably, the resulting lenses were structurally identical to the original ones and expressed similar levels of lens-specific genes. Subsequent analysis revealed that the transcriptomes of young and old (19-times regenerated) lenses are nearly indistinguishable, showcasing the robustness of newt lens regeneration. Of note, by the end of the study the specimens were at least 30 years old, representing a geriatric population in this species. This provides an interesting contrast to the declines in regenerative capacities observed in most vertebrate contexts.

Additional studies indicate that repetitive amputations do not affect tail regenerative potential in the newt Triturus carnifex, as examined over a 10 year period with up to nine tail regeneration cycles, nor that of the axolotl limb, challenged by five regeneration rounds during 3 years. Taken together, the evidence to date suggests that the ability of urodeles to regenerate complex structures does not decline with time or serial regeneration cycles. In mammals, loss of regenerative potential with ageing has been largely attributed to the ageing of stem cell populations and/or their niche. Whether the prevalence of dedifferentiation as a regenerative mechanism in salamanders is linked to the indefinite nature of their regenerative potential remains an outstanding question.

Beyond their remarkable regenerative abilities, salamanders exhibit extraordinary longevity, constituting lifespan outliers with respect to organismal size. Among animal species, there is a notable correlation between body mass and lifespan, with larger animals living longer. Yet, salamanders break this rule by several orders of magnitude. For example, axolotls - average mass: 60-110g - live over 20 years, and cave olms - Proteus anguinus; average mass: 17g - can surpass 100 years. Indeed, they match and in some cases exceed the lifespan/body mass ratios found in other well-known outliers such as the naked mole rat and Brandt's bat. This is even more remarkable given that most salamander longevity data derive from specimens in the wild, where animals are exposed to environmental challenges, predation, pathogens, and food source fluctuations. Thus, salamanders are not only lifespan outliers, but also in many cases their longevity may be underestimated.

It should not be surprising to find correlations between manifestations of age-related degeneration, even those in which it is debatable as to whether age-related condition A can contribute meaningfully to the progression of age-related condition B, as is the case for hearing loss and physical frailty. All age-related conditions and aspects of aging arise from the same set of underlying forms of cell and tissue damage. Different people accumulate that damage at somewhat different rates, due largely to lifestyle choices and environmental factors. If someone exhibits greater consequences of aging in one part of the body, the odds are good that degeneration in the rest of the body is also more advanced.

Physical functioning is necessary for independent living and tends to decline with age. Hearing impairment, which affects approximately two-thirds of adults older than 70 years, is a risk factor for various adverse outcomes. Hearing impairment may also adversely affect physical functioning through reduced perception of auditory input that contributes to walking and balance. However, research characterizing the association between hearing impairment and objective physical function and walking endurance measures is limited.

Associations between self-reported hearing impairment and poorer physical function have been reported previously. However, self-reported hearing impairment is prone to measurement error and has been shown to underestimate associations with objective measures of function. Although studies with audiometrically assessed hearing, the criterion-standard clinical measure, have revealed associations with slower gait and poorer physical function, these studies did not assess associations with physical function components separately. Therefore, we investigated the association of hearing impairment with physical function and walking endurance in a cohort of community-dwelling older adults in the US.

In this cohort study, hearing impairment was associated with poorer physical function and walking endurance in cross-sectional analysis and faster declines in physical function in longitudinal analysis. These associations were graded in general, with stronger associations among individuals with worse hearing. The differences in gait speed and walking endurance between participants with severe hearing impairment vs those with normal hearing were clinically meaningful according to previous literature. Collectively, these findings suggest that individuals with hearing impairment may be at greater risk for physical function limitations.

Link: https://doi.org/10.1001/jamanetworkopen.2021.13742

This research into the fine details of hair greying is interesting but of limited practical application, I suspect. It is nonetheless a good illustration of the point that there are few sharp dividing lines in the biochemistry of aging. Even seemingly binary changes such as hair going grey represent a broad threshold that is crossed slowly, and under the hood there are likely numerous competing and conflicting mechanisms and regulatory systems that only incrementally come to a consensus on cell behavior. None of this really changes the best way forward for the treatment of any part of aging: identify the causative damage and repair that damage, in the expectation that many of the consequences that make up degenerative aging will reverse themselves as cell behavior returns to a youthful state.

Hair greying is a visible sign of aging that affects everyone. The loss of hair color is due to the loss of melanin, a pigment found in the skin, eyes and hair. Research in mice suggests stress may accelerate hair greying, but there is no definitive research on this in humans. This is because there are no research tools to precisely map stress and hair color over time. But, just like tree rings hold information about past decades, and rocks hold information about past centuries, hairs hold information about past months and years.

Hair growth is an active process that happens under the skin inside hair follicles. It demands lots of energy, supplied by structures inside cells called mitochondria. While hairs are growing, cells receive chemical and electrical signals from inside the body, including stress hormones. It is possible that these exposures change proteins and other molecules laid down in the growing hair shaft. As the hair grows out of the scalp, it hardens, preserving these molecules into a stable form. This preservation is visible as patterns of pigmentation. Examining single-hairs and matching the patterns to life events could allow researchers to look back in time through a person's biological history.

Researchers here report a new way to digitize and measure small changes in color along single human hairs. This method revealed that some white hairs naturally regain their color, something that had not been reported in a cohort of healthy individuals before. Aligning the hair pigmentation patterns with recent reports of stress in the hair donors' lives showed striking associations. When one donor reported an increase in stress, a hair lost its pigment. When the donor reported a reduction in stress, the same hair regained its pigment. Researchers mapped hundreds of proteins inside the hairs to show that white hairs contained more proteins linked to mitochondria and energy use. This suggests that metabolism and mitochondria may play a role in hair greying.

The new method for measuring small changes in hair coloring opens up the possibility of using hair pigmentation patterns like tree rings. This could track the influence of past life events on human biology. In the future, monitoring hair pigmentation patterns could provide a way to trace the effectiveness of treatments aimed at reducing stress or slowing the aging process. Understanding how 'old' white hairs regain their 'young' pigmented state could also reveal new information about the malleability of human aging more generally.

Link: https://doi.org/10.7554/eLife.67437

Today's open access paper provides an interesting example of a mechanism that slows a facet of aging only in middle age, when tested in mice. Researchers found that upregulation of NRF2 expression in the brain via gene therapy had meaningful positive effects on neural stem cell function in middle age only. We might consider that any given aspect of cell behavior is governed by multiple overlapping regulatory networks, and thus it is quite possible to see a particular point of intervention work under some circumstances but not under others, depending on the state of the cell, its environment, and which regulatory systems are dominant as a consequence.

Neural stem cells provide a supply of new neurons to the brain, which is very important for tissue maintenance, recovery from injury, and the workings of memory, among other processes. These stem cell populations, like all others elsewhere in the body, decline in activity with age. Much of this is a reaction to the molecular damage of aging throughout the body and consequent changes in the signaling environment, rather than any critical inherent damage to the stem cells themselves. Thus a broad range of strategies in medical research aim to force stem cells into greater, more youthful levels of activity, overriding their controlling mechanisms in order to do so. It remains to be seen as to the degree that the risk of cancer, due to increased cell activity in an environment of increased cell damage, is a problem that will significantly limit the use of this approach in any given case.

Enhanced NRF2 expression mitigates the decline in neural stem cell function during aging

Adult neural stem progenitor cells (NSPCs) are characterized by the ability to self-renew and differentiate into neuronal and glial cell types in the mature nervous system. This cell-level plasticity is not fixed, but rather a dynamic and highly modulated process. NSPC activity can be influenced by a range of factors, such as physical exercise, environmental enrichment, stress, and nutrition, but also importantly aging. In fact, aging contracts NSPC niches in the brain and significantly alters their function. Given the pivotal role of stem cells in tissues with lifelong regenerative capacity such as the brain, understanding stem cell aging will be important if we are to understand aging at the organ level. More broadly, comprehending stem cell aging will also support the development of interventions that could improve both health and lifespan.

In this context, our previous studies, conducted in naturally aging rodents, identified a specific temporal pattern of change in NSPC dynamics during aging. In particular, the studies highlighted a critical time during middle age (13-15 months), when the regenerative function of NSPCs showed a striking decline. The studies also determined the reduced expression of nuclear factor (erythroid-derived 2) like 2 (or NRF2), as a key mechanism mediating this phenomenon. As such, this work provided first evidence of an important regulatory role for NRF2 in NSPC aging.

NRF2 is a redox-sensitive transcription factor known to be essential to the cell's homeostatic mechanism. NRF2 is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, inflammatory agents, and excessive nutrient/metabolite supply. In particular, NRF2 can up-regulate a range of classical ARE (antioxidant response element)-driven genes, encoding major antioxidants and other detoxification enzymes. In addition to its classical function in regulating the stress response, NRF2 has been linked to cell growth, proliferation, mitochondrial and trophic functions, protein quality control, and increased lifespan.

Given that NRF2 loss accentuates NSPC aging, in this study, we investigated whether increasing NRF2 levels could boost NSPC function with age. In particular, we studied whether inducing high intrinsic NRF2 expression can potentially mitigate the decline in NSPC regeneration during the critical middle-age period between 13 and 15 months, identified in our previous work. NRF2 was delivered to rat subventricular zone (SVZ) NSPCs through recombinant adeno-associated viral (AAV) vectors injected either before (at 11 months of age) or well after the critical aging period (at 20 months of age). We find that the administration of AAV-NRF2-eGFP vectors before the initiation of the critical period substantially improved SVZ NSPC regeneration and associated behavioral function, as compared to controls (AAV-eGFP delivery). On the other hand, application of AAV-NRF2-eGFP after the conclusion of the critical period failed to significantly promote NSPC activity and function. This data establishes a major governing role for NRF2 in NSPCs and support targeting the NRF2 pathway as a potential approach to advantageously modulate NSPC function with age.

A eusocial species is divided into specialized castes. The reproductive caste (queens) exhibits a much longer life span than members of the other non-reproductive castes (workers), yet the members of all castes are genetically similar. Researchers here discuss the ways in which this divergent life span might evolve so reliably whenever a species is eusocial. It is observed across widely divergent species, from insects to mammals. This sort of work complements investigations into the biochemistry of this exceptional longevity of the reproductive caste, mostly carried out in insect species.

Queens of eusocial species live extraordinarily long compared to their workers. So far, it has been argued that these lifespan divergences are readily explained by the classical evolutionary theory of ageing. As workers predominantly perform risky tasks, such as foraging and nest defense, and queens stay in the well-protected nests, selection against harmful genetic mutations expressed in old age should be weaker in workers than in queens due to caste differences in extrinsic mortality risk, and thus, lead to the evolution of longer queen and shorter worker lifespans. However, these arguments have not been supported by formal models.

Here, we present a model for the evolution of caste-specific ageing in social insects, based on the antagonistic pleiotropy theory of ageing. In individual-based simulations, we assume that mutations with antagonistic fitness effects can act within castes, that is, mutations in early life are accompanied by an antagonistic effect acting in later life, or between castes, where antagonistic effects emerge due to caste antagonism or indirect genetic effects between castes. In monogynous social insect species with sterile workers, large lifespan divergences between castes evolved under all different scenarios of antagonistic effects, but regardless of the degree of caste-specific extrinsic mortality. Mutations with antagonistic fitness effects within castes reduced lifespans of both castes, while mutations with between-caste antagonistic effects decreased worker lifespans more than queen lifespans, and consequently increased lifespan divergences.

Our results challenge the central explanatory role of extrinsic mortality for caste-specific ageing in eusocial organisms and suggest that antagonistic pleiotropy affects castes differently due to reproductive monopolization by queens, hence, reproductive division of labor.

Link: https://doi.org/10.1002/evl3.230

Age-related disease results from the underlying cell and tissue damage that causes aging. Different people accumulate that damage at modestly different rates, the result of lifestyle choices and exposure to infectious disease. Thus the presence of a sufficient burden of damage to produce one age-related disease will be accompanied by a raised risk of other age-related conditions. The conditions themselves need not have any direct relationship with one another, but can be distinct outcomes of the same root causes. Here, however, researchers propose that heart failure may provoke increased cancer risk via inflammatory and other signaling pathways. This may or may not be the case. The inflammatory signaling certainly exists, but it is always a challenge to determine the relative significance of the many possible contributing mechanism in the onset and progression of age-related disease.

Our study demonstrates that heart failure patients have a significantly increased incidence of cancer in general and of each individual cancer type studied. The data - based on a collective of over 100,000 heart failure patients - confirm the results of previous evaluations in smaller study populations. The data do not prove a causal relationship but instead show a statistical relationship between heart failure and cancer. Nevertheless, these results allow us to speculate that there may be a causal relationship between heart failure and an increased cancer rate.

The particularly high incidence of oropharyngeal carcinoma in heart failure patients suggests that common extrinsic risk factors such as nicotine are a possible trigger of the co-morbidity. In this regard, one limiting factor of our study is that our database does not provide data on nicotine use or alcohol consumption. In addition to these external risk factors, cancer in general and cardiovascular diseases share common risk factors such as obesity and diabetes. As our data are adjusted for these risk factors, our highly significant results cannot be explained by these factors alone.

One possible explanation could be the occurrence of certain pathomechanisms such as chronic inflammation or increased free radical formation, which may interact with a certain genetic background to connect both heart failure and cancer. Another interesting hypothesis suggests that heart failure is an oncogenic condition. This means that the failing heart may promote tumourigenesis or tumour growth. New data from animal studies suggest that the secretion of certain proteins may be up-regulated in failing hearts, promoting the secretion of certain tumour growth factors.

Supporting evidence comes from a study demonstrating that serum levels of heart failure markers such as N-terminal pro-brain natriuretic peptide and troponin T were elevated in cancer patients even before the application of anticancer therapy, suggesting that subclinical myocardial injury exists in cancer patients. The specific interaction of cardiac stress-induced proteins with oncogenic signalling pathways is a relatively new branch of research with great potential. Some of these potential heart failure / oncogenic pathway interactions may be organ specific. In this context, studies such as ours that link large collectives of heart failure patients not only to cancer development in general but also to individual organ systems may be helpful.

Link: https://doi.org/10.1002/ehf2.13421