Fight Aging! Newsletter, January 31st 2022

Inflammation is a critical aggravator of neural injury following brain insults. In the aged brain, microglia exhibit an exaggerated and uncontrolled inflammatory phenotype in response to brain insults or immune stimulation. Rather than an enhanced immune response at baseline level, aged microglia possess a primed profile that is demonstrated by augmented production of inflammatory factors such as interleukin (IL)-1β and reactive oxygen species following stimulus. Although evidence suggests a link between the primed profile of the aged microglia and vulnerability of the old brain to inflammation-related secondary injury following acute insult, it remains poorly understood to what extent the aged microglia with a primed profile can impact the neuroinflammation and the outcome of acute brain injury.

The survival of microglia critically depends on signaling through the colony-stimulating factor 1 receptor (CSF1R). Administration of CSF1R inhibitor PLX3397 eliminates microglia in the whole brain that continues when CSF1R inhibition is present. Moreover, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells, leading to effective replacement of the entire microglia population, a process takes approximately 2-3 weeks to complete.

Recent evidence suggests that withdrawal of CSF1R inhibitors in the old mice leads to complete repopulation of new microglia with characteristics resembling young microglia. Therefore, withdrawal of CSF1R inhibitors in the old brain resets the primed microglia and provides an opportunity to determine the impact of aged microglia on neural injury upon brain insults. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection.

We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α, and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.

Currently the single disease paradigm is still dominant in medicine in general, and also plays a major role in geriatric reasoning. This paradigm (sometimes referred to as Occam's razor) aims to explain illness by looking at patients´ symptoms (subjective: e.g. pain) and clinical signs (objective: e.g. high blood pressure) in specific patient episodes and by linking these with a single disease. Thus, clinicians aim to identify the single best cause for a patient's constellation of symptoms. Diagnostic reasoning in geriatrics should however take into account the high prevalence of multimorbidity, which increases with age from around 10% at the age of 40 to 85% in those aged 75 and over. In older adults with multimorbidity, a single symptom may arise from multiple diseases (e.g. fatigue may arise from both heart failure and osteoarthritis). Parallel treatment of single diseases easily leads to a high total treatment burden, over-treatment and aggravation of disease burden due to drug-drug, drug-disease, and drug-nutrition interactions. Thus, in case of multimorbidity, the cumulative single disease approach is often inefficient and potentially harmful.

Despite the great urgency, geriatric medicine still lacks a valid and clinically applicable model for adequate diagnosis, prognosis, and treatment of multimorbidity. Commonly used epidemiological methods try to explain multimorbidity pathophysiology by using sum scores, morbidity indices, and clustering of diseases. Clinically, multimorbidity is taken into account by cumulative (sometimes weighted) comorbidity scores, if considered at all. However, these epidemiology-based methods all fail to capture the dynamics and complexity of multimorbidity and its impact on the individual patient. Moreover, these methods are quantitative, abstract figures that do not inform clinical decision-making and thus are of limited added value in clinical practice. Even the most advanced models still rely on clustering of single disease concepts, and do not explain the interactions in multiple organ systems.

Complex systems thinking implies that illness in case of multimorbidity is not caused by a simple sum of single diseases and may offer an alternative explanatory model to the biomedical model. The science serving this field is devoted to understanding the general properties of complex systems. Core hallmarks of complex systems include: [1] networks of interacting elements (e.g. interactions among aging mechanisms such as oxidative stress and amyloid aggregation in dementia or decreased mobility, depressed mood, and joint pain), [2] feedback/feedforward loops (e.g. adaptive loops such as blood pressure regulation and maladaptive loops such as higher inflammatory states in Alzheimer's disease or older COVID-19 patients), [3] a multiscale or modular hierarchical structure (e.g. accumulating cellular damage nested within organ tissue, within organisms and families), [4] non-linear dynamics (e.g. tipping points in disease trajectories that cause acute flipping from dementia to a delirious state) and [5] emergent properties: the sum of properties of system components is not equal or even similar to the whole system outcome (e.g. well-being and illness cannot be understood simply as the sum of multiple morbidities as we diagnose them when they occur individually).

We therefore propose to develop clinical dynamic symptom network (DSN) based using principles of complexity science and network analysis. First evidence for the clinical utility of this approach comes from mental health research, in which the single disease model often fails and complex psychological symptom networks have advanced understanding and treatment of mental disorders. DSNs may form the foundation of a new paradigm to understand and treat geriatric illness episodes and trajectories. These should not replace geriatric syndromes or disease thinking, but may have a strong synergistic value, as thinking in symptoms and an illness concept may be more closely related to improving well-being outcomes in older patients. In future research, DSNs may be used to: (i) understand the complex, time-varying interrelations of symptoms, signs and diseases; (ii) develop prognostic models for changes in symptoms, signs and diseases over time; and (iii) evaluate effects of therapeutic interventions on the total symptom burden.

Age-related gut barrier dysfunction and dysbiosis of the gut microbiome play crucial roles in human aging. Dietary methionine restriction (MR) has been reported to extend lifespan and reduce the inflammatory response; however, its protective effects on age-related gut barrier dysfunction remain unclear. Accordingly, we focus on the effects of MR on inflammation and gut function.

We found a 3-month methionine-restriction reduced inflammatory factors in the serum of aged mice. Moreover, MR reduced gut permeability in aged mice and increased the levels of the tight junction proteins mRNAs, including those of occludin, claudin-1, and zona occludens-1. MR significantly reduced bacterial endotoxin lipopolysaccharide concentration in aged mice serum.

By using 16s rRNA sequencing to analyze microbiome diurnal rhythmicity over 24 hour, we found MR moderately recovered the cyclical fluctuations of the gut microbiome which was disrupted in aged mice, leading to time-specific enhancement of the abundance of short-chain fatty acid-producing and lifespan-promoting microbes. Moreover, MR dampened the oscillation of inflammation-related TM7-3 and Staphylococcaceae.

In conclusion, the effects of MR on the gut barrier were likely related to alleviation of the oscillations of inflammation-related microbes. MR can enable nutritional intervention against age-related gut barrier dysfunction.

In the new study, researchers tested the idea that increased senescence within the neural stem cell niche negatively impacts adult neurogenesis, focusing on the middle-aged mouse brain. They observed an aging-dependent accumulation of senescent cells, largely senescent stem cells, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of the senescent cells via a drug called ABT-263 caused a rapid increase in normal stem cell proliferation and neurogenesis, and genetic ablation of senescent cells similarly activated hippocampal stem cells.

This burst of neurogenesis had long-term effects in middle-aged mice. One month after treatment with ABT-263, adult-born hippocampal neurons increased and hippocampus-dependent spatial memory was enhanced. "The surprise for us is that only one injection of the drug was sufficient to mobilize the normal stem cells in the hippocampus, and it did so after only 5 days. The newly awakened stem cells continued to function well for the next 30 days."

These results support the idea that the aging-dependent accumulation of senescent cells, including senescent stem cells in the hippocampal niche, negatively affects normal stem cell function and adult neurogenesis, contributing to an aging-related decline in hippocampus-dependent cognition. Moreover, the results provide a potential explanation for the previously observed age-related decreases in hippocampal stem cells and neurogenesis. A large proportion of stem cells becomes senescent, making them unavailable to generate new neurons, and these senescent stem cells likely adversely affect neurogenesis from their non-senescent neighbors.

Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on central nervous system (CNS) neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs.

This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.

Biological age is an important concept, albeit a slippery one. Everyone's physical and mental functioning gradually declines from early adulthood onwards, but this occurs at different rates in different people. A technique for measuring biological age detects a signal that is a better guide to a person's functional capacity than their actual, chronological age. As more and more scientists seek to slow, halt or rewind ageing, such methods will be needed to assess whether the new manipulations achieve these goals.

Epigenetic clocks use algorithms to calculate biological age on the basis of a read-out of the extent to which dozens or even hundreds of sites across an individual's genome are bound by methyl groups - a form of epigenetic modification. In 2019, a small study raised the tantalizing prospect that ageing could be reversed. Scientists gave 9 men aged 51 to 65 a growth hormone and two diabetes medications for a year. The drugs seemed to rejuvenate the men's thymus glands and immune function. They also shaved 2.5 years off the men's biological age, as measured by epigenetic clocks.

The study is one of many, in humans and in animals, that seek ways to reduce epigenetic clock scores - and thereby develop new anti-ageing interventions. But some experts are concerned by the unknowns that still surround this technology. "It's become a sort of dogma in the field - and in the popular perception - that these things are really measuring biological ageing. We really need to understand how these things are working. That's the weakness of these biomarkers. They come out of a machine-learning algorithm. They work beautifully in a mathematical sense, but biologists want more."

The US Food and Drug Administration does not currently recognize epigenetic clock scores as surrogate end points for clinical trials. It wants their mechanistic basis to be better defined. And it wants an answer to the crucial question of whether a short-term decrease in someone's epigenetic clock score definitively lowers their chances of developing age-related ill health.

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases.

This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

Over half of UK adults over the age of 65 live with two or more long-term health conditions - commonly known as multimorbidity. Crucially, over half of GP consultations and hospital appointments involve patients with multimorbidity. In the UK, care for people with multimorbidity is also estimated to take up to 70% of health and social care expenditure.

Multimorbidity is currently managed by treating each disease separately. This means people will need to take multiple medications at the same time (known as polypharmacy), and will also have to attend multiple medical appointments for each condition. Not only can this put a strain on the NHS, polypharmacy can also put patients at increased risk of negative drug interactions and unintended harm. There's a clear need to improve the way multimorbidity is treated. But research shows that to do this, we need to instead start looking at targeting the key causes of multimorbidity when searching for treatments.

Although multimorbidity differs for each person, we know that patients tend to suffer from the same groups of diseases - known as "clusters". This suggests that each cluster may share a common underlying cause. For example, a person with multimorbidity may suffer from heart problems (such as heart disease and high blood pressure) and diabetes, which may all stem from the same cause - such as obesity. Identifying and treating the cause of a patient's disease clusters would allow us to more effectively combat several - or even all - of the diseases a patient has using a single treatment.

Such an approach has not yet been taken, in large part because medical research and drug discovery tends to focus on treating a single disease. Importantly one of the biggest risk factors for developing multimorbidity is getting older. This is why researchers think targeting the biological causes of ageing could be one way of treating multimorbidity, by preventing clusters of diseases from developing in the first place.

For example, we become less able to remove senescent cells from our body as we get older, causing them to accumulate and increase our risk of disease. Researchers think that if we could prevent these cells from building up, we may be better able to prevent multimorbidity from happening to begin with. Drugs which can kill senescent cells (called senolytics) already exist, and are currently used to treat certain types of leukaemia, and are now being trialled on patients with the chronic lung condition idiopathic pulmonary fibrosis. Given that senolytics are already in clinical use, this means they could quickly be repurposed for use in patients with multimorbidity if proven to be effective on other conditions too.

Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intramuscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model.

In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development.

Many biomarkers have been shown to be associated not only with chronological age but also with functional measures of biological age. In human populations, it is difficult to show whether variation in biological age is truly predictive of life expectancy, as such research would require longitudinal studies over many years, or even decades. We followed adult cohorts of 20 Drosophila Genetic Reference Panel (DGRP) strains chosen to represent the breadth of lifespan variation, obtain estimates of lifespan, baseline mortality, and rate of aging, and associate these parameters with age-specific functional traits including fecundity and climbing activity and with age-specific targeted metabolomic profiles.

We show that activity levels and metabolome-wide profiles are strongly associated with age, that numerous individual metabolites show a strong association with lifespan, and that the metabolome provides a biological clock that predicts not only sample age but also future mortality rates and lifespan. This study with 20 genotypes and 87 metabolites, while relatively small in scope, establishes strong proof of principle for the fly as a powerful experimental model to test hypotheses about biomarkers and aging and provides further evidence for the potential value of metabolomic profiles as biomarkers of aging.

A growing body of evidence suggests that the network of small vessels (microvasculature) in the retina might be a reliable indicator of the overall health of the body's circulatory system and the brain. While the risks of illness and death increase with age, it's clear that these risks vary considerably among people of the same age, implying that 'biological ageing' is unique to the individual and may be a better indicator of current and future health, say the researchers.

Researchers turned to deep learning to see if it might accurately predict a person's retinal age from images of the fundus, the internal back surface of the eye, and to see whether any difference between this and a person's real age, referred to as the 'retinal age gap', might be linked to a heightened risk of death. The researchers drew on 80,169 fundus images taken from 46,969 adults aged 40 to 69, all of whom were part of the UK Biobank, a large, population-based study of more than half a million middle aged and older UK residents. Some 19,200 fundus images from the right eyes of 11,052 participants in relatively good health at the initial Biobank health check were used to validate the accuracy of the deep learning model for retinal age prediction.

This showed a strong association between predicted retinal age and real age, with an overall accuracy to within 3.5 years. The retinal age gap was then assessed in the remaining 35,917 participants during an average monitoring period of 11 years. During this time, 1,871 (5%) participants died: 321 (17%) of cardiovascular disease; 1018 (54.5%) of cancer; and 532 (28.5%) of other causes including dementia. The proportions of 'fast agers' - those whose retinas looked older than their real age - with retinal age gaps of more than 3, 5, and 10 years were, respectively, 51%, 28%, and 4.5%. Each 1 year increase in the retinal age gap was associated with a 2% increase in the risk of death from any cause.

When folded correctly, proteins carry out their functions and remain soluble in the environment of the cell. Misfolded proteins, by contrast, cannot function properly and tend to stick to each other and other proteins, clogging up cellular processes and generating toxic aggregates. Protein aggregation has been specifically implicated in a wide variety of aging-linked diseases, including Alzheimer's, Parkinson's, frontotemporal dementia, Huntington's disease, and ALS (amyotrophic lateral sclerosis).

To guard against the continual production of misfolded proteins, cells have dedicated "quality control" machinery for fixing or degrading misfolded proteins. Previous research has shown that shortcomings in these processes can lead to aggregation. This research is the first to show the folding defect during ageing starts early in the journey of a protein, when it is made by the ribosome. Because ribosomes are constantly producing large amounts of proteins, these defects cause a subsequent snowball of disfunction.

To start, the researchers used a technique called ribosome profiling, which allowed them to see exactly how ribosomes are moving on the messenger RNA during the act of translation. Amassing data from all the genes translated in young and aged Caenorhabditis elegans roundworms and yeast, the researchers noticed that in older cells ribosomes periodically moved more slowly and were more likely to stall and bump into each other. As one might expect, the researchers saw that decreases in proper ribosome performance aligned with increases in the aging-dependent aggregation of misfolded proteins. One important insight was that the increase in stalling and misfolding overwhelmed the cell's cleaning-up-and-clearing-out quality control failsafes.

In follow-up experiments in worms, the researchers found that even if the overall fraction of newly made proteins with altered translation during aging is low (~10%), this small effect can still be enough to overwhelm the quality control system and trigger significant aggregation that can disrupt many different cellular components or processes. "Every cell normally makes millions of these newly translated proteins. So very slight changes in the efficiency of folding with age will escalate in a vicious cycle where defects in translation lead to an overload of the system, which in turn leads to increased protein aggregates with age that are themselves also toxic."

Intermittent fasting and caloric restriction (IF and CR) are effective therapies against obesity and its complications, including non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, in mice and in humans. However, intensive lifestyle modifications are rarely sustainable in real-world settings. We previously found that the hepatocyte response to glucose deprivation is sufficient to mimic several key therapeutic effects of generalized IF and CR on hepatic steatosis, hepatic inflammation, and insulin resistance, in part by inducing hepatocyte autophagic flux and secretion of the anti-diabetic hepatokine, FGF. We thus set out here to leverage this pathway against metabolic disease. Clinically, this approach is of particular interest, because hepatocyte glucose transport and its downstream pathways are amenable to pharmacological therapy.

We previously identified the arginine ureahydrolase, arginase 2 (ARG2), as a hepatocyte glucose withdrawal-induced factor. Induction of ARG2 is sufficient to exert part of the therapeutic metabolic sequelae of caloric restriction. Subsequent data further demonstrated that arginase 1 and arginase 2 polymorphisms determine circulating arginine levels in arginine-supplemented and unsupplemented dietary contexts. Together, the data initiated the hypothesis that augmenting arginine catabolism can modulate host arginine status - and thereby therapeutically direct energy metabolism.

Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase, arcA, promotes mammalian energy expenditure and insulin sensitivity and reverses dyslipidemia, hepatic steatosis, and inflammation in obese mice. Extending this, pharmacological arginine catabolism via pegylated arginine deiminase (ADI-PEG 20) recapitulates these metabolic effects in dietary and genetically obese models. These effects require hepatic and whole-body expression of the autophagy complex protein BECN1 and hepatocyte-specific FGF21 secretion. The data thus reveal an unexpected therapeutic utility for arginine catabolism in modulating energy metabolism by activating systemic autophagy, which is now exploitable through readily available pharmacotherapy.

Urolithin A is a byproduct of a person's gut bacteria and a diet comprising polyphenols found in pomegranates, berries, and nuts. Supplemental urolithin A has been shown in animal tests and molecular studies of humans to stimulate mitophagy. Researchers studied a small cohort of people over age 65 who were randomized to receive a placebo or a daily supplement of 1,000 mg urolithin A for four months. Each of the 66 subjects was confirmed at the outset to have average or subpar capacity to produce adenosine triphosphate (ATP), which mitochondria produce to help cells perform myriad functions. The investigators hypothesized that, if the urolithin A supplement indeed boosted mitophagy, the test cohort would experience improved muscle function and greater ATP output.

Across both cohorts, two comparisons of muscle function were found to support the thesis, but two others did not. Two measures of muscle endurance were improved in the supplemented group compared to the placebo group. Endurance was measured with exercises involving the hand and leg. Researchers measured the increase in the number of muscle contractions until fatigue between a baseline test and the final test four months later. Measures of distance covered during a six-minute walk improved markedly between tests at baseline and four months in both the supplement and placebo groups. However, researchers saw no significant effect of the supplement compared with the placebo. Measures (via magnetic resonance spectroscopy) of improvement of maximal ATP production did not change significantly between baseline and four months in either group.

Plasma samples also were collected from study participants at the outset, at two months and four months. The purpose was to assess supplement's potential effect on urolithin A bioavailability and on biomarkers of mitochondrial health and inflammation. In the test cohort, Urolithin A was associated with a significant reduction in several acylcarnitines and ceramides implicated for their roles in metabolic disorders involving mitochondria. "These changes suggest that the treatment affects the metabolic condition of people. Even though it didn't affect the maximum ATP production, it improved test subjects' general metabolism."

The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression.

We used the reprogrammable mice known as i4F-B which carries a ubiquitous doxycycline-inducible OSKM transgene, abbreviated as i4F. Mice of both sexes were used, and of different ages; young (females, 13 weeks), old (females, 55 weeks) and very old (males and females, 100 weeks). Doxycycline was administered in the drinking water for a period of 7 days. Mice were sacrificed two or four weeks after doxycycline removal.

We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.

The relationship between immunosenescence and inflammageing is complex, involving the interplay between innate and adaptive arms of the immune system, together with senescent cells from non-immune system lineages, in a potentially vicious cycle. Inflammageing promotes senescence and impedes adaptive immune responses, while this impairment may lead to a greater mobilisation of innate immune cells, thereby favouring inflammageing. With the ageing of the immune system, immunosurveillance becomes less efficient, leading to failure to remove senescent cells. These in turn contribute locally and systemically to inflammation. The evidence discussed above demonstrates an overall imbalance in inflammatory processes, tilting progressively towards increasing inflammation with age, with failure of anti-inflammatory molecules to counteract this. The important interconnections between inflammation, immunosenescence, frailty, and age-related disease have been highlighted further by the development of an accurate ageing clock (iAge) based on inflammatory signatures.

The need to improve immune health and resistance to infectious diseases in older adults has been brought into sharp focus by the COVID-19 pandemic. Herein, we have outlined several strategies to improve elderly immune function and decrease inflammation. Of these, spermidine treatment, mTOR inhibition, and the selective removal of senescent cells using senolytics are most strongly supported by model organism studies and human clinical trial data, with significant scope for immune benefit even against severe infections, such as that caused by SARS-CoV-2. It is possible that combinations of these therapies may be needed to address immunosenescence and inflammageing in the context of an ageing body burdened with accumulated senescent cells.

We recommend that clinical trials of drugs for age-related diseases routinely include analysis of inflammatory mediators in order to determine whether the treatment has the added benefit of ameliorating inflammageing. We conclude that it is essential to investigate a diverse set of inflammation-related molecules to properly analyse the development of chronic inflammation with ageing; new proteomics platforms that permit simultaneous measurement of thousands of factors from very small samples should greatly facilitate such analysis and enable personalised interventions to reduce inflammation and support healthy immune function even in old age.