Fight Aging! Newsletter, July 19th 2021

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."

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.

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.

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.

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.

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.

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 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.

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.

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."

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 that explain how androgens drive male-accelerated aging.

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.

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.

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.

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.

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 systemss://en.wikipedia.org/wiki/Model_organism">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.

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.