Fight Aging! Newsletter, September 23rd 2024

This study aimed to appraise existing research using retinal photography to develop biological ageing markers. We sought to determine the accuracy of retinal age prediction models, evaluate their ability to reflect age-related parameters and explore their clinical associations. This scoping review identified models which estimate chronological age from retinal images with moderate to high accuracy and identified several age-related associations.

Four models are currently available to estimate biological age from retinal images, all based on deep learning algorithms: 'Retinal Age', 'EyeAge', 'convolutional network-based model', and 'RetiAGE'. 'Retinal Age', 'EyeAge', and 'convolutional network-based model' were trained to predict numerical chronological age from retinal images, while 'RetiAGE' was trained to predict the probability of an individual being older than 65 years.

All models were trained and validated using a single dataset, predominantly comprising Caucasian or Asian populations. To enhance robustness, both 'EyeAge' and 'RetiAGE' underwent additional internal testing on previously unseen images from the training and validation cohort. For model testing and outcome assessment, the UK Biobank was used by three models: 'Retinal Age', 'EyeAge' and 'RetiAGE'. While the four identified models demonstrated comparable accuracy and performance, it is important to highlight inconsistent reporting of performance metrics, with some pertaining to validation performance, and others test performance. Consequently, the generalisability of these models is uncertain, warranting further work to assess their applicability across diverse populations.

Nevertheless, using retinal age models to predict mortality and morbidity carries significant clinical implications. A key finding from selected papers emphasises that accelerated ageing, calculated as retinal age gap (RAG), age acceleration or other indices, consistently correlates with mortality risk across three models. In addition, 'Retinal Age' and 'EyeAge' show associations with cardiovascular disease, while 'Retinal Age' and 'convolutional network-based model' show connections with the risk of diabetic retinopathy in patients with diabetes. These findings highlight the potential of retinal age as an informative tool for quantifying risk of mortality and cardiovascular morbidity. However, no clinical trials have yet explored the utility or feasibility of the models, a crucial aspect for determining their clinical relevance. Furthermore, factors associated with higher RAG, including glycaemic status, central obesity, and metabolic syndrome, suggest that RAG may provide valuable insight into lifestyle habits and traits that accelerate ageing.

Gut microbiota of centenarians has garnered significant attention in recent years, with most studies concentrating on the analysis of microbial composition. However, there is still limited knowledge regarding the consistent signatures of specific species and their biological functions, as well as the potential causal relationship between gut microbiota and longevity. To address this, we performed the fecal metagenomic analysis of eight longevous populations at the species and functional level, and employed the Mendelian randomization (MR) analysis to infer the causal associations between microbial taxa and longevity-related traits.

We observed that several species including Eisenbergiella tayi, Methanobrevibacter smithii, Hungatella hathewayi, and Desulfovibrio fairfieldensis were consistently enriched in the gut microbiota of long-lived individuals compared to younger elderly and young adults across multiple cohorts. Analysis of microbial pathways and enzymes indicated that E. tayi plays a role in the protein N-glycosylation, while M. smithii is involved in the 3-dehydroquinate and chorismate biosynthesis. Furthermore, H. hathewayi makes a distinct contribution to the purine nucleobase degradation I pathway, potentially assisting the elderly in maintaining purine homeostasis. D. fairfieldensis contributes to the menaquinone (vitamin K2) biosynthesis, which may help prevent age-related diseases such as osteoporosis-induced fractures.

According to MR results, Hungatella was significantly positively correlated with parental longevity, and Desulfovibrio also exhibited positive associations with lifespan and multiple traits related to parental longevity. Additionally, Alistipes and Akkermansia muciniphila were consistently enriched in the gut microbiota of the three largest cohorts of long-lived individuals, and MR analysis also suggests their potential causal relationships with longevity. Our findings reveal longevity-associated gut microbial signatures, which are informative for understanding the role of microbiota in regulating longevity and aging.

The myelination of axons by oligodendrocytes in the central nervous system (CNS) is essential for proper nervous system function. Mature oligodendrocytes are post-mitotic and arise through a stepwise differentiation process from resident oligodendrocyte progenitor cells (OPCs). Oligodendrocytes that arise during development may have very long lifespans, perhaps equal to the longevity of the animal itself; it is, therefore, curious that a remarkable ~5% of all cells in the adult CNS remain as OPCs. This resident pool of OPCs represents a potential source of new oligodendrocytes important for cognition and learning and also to replace those lost to injury or inflammation in diseases such as multiple sclerosis (MS).

Proteins of the C1q/tumor necrosis factor (TNF) superfamily have recently gained attention for their role at neuronal synapses. Among these, the complement C1q-like (C1QL) proteins, encoded by four paralogous genes (C1ql1, C1ql2, C1ql13, C1ql14), have drawn significant interest. In the CNS, C1QL proteins are typically expressed in a small subset of neurons, are secreted from pre-synaptic terminals, reside in the synaptic cleft, and function to promote synapse formation and/or maintenance. We have determined that C1QLs bind to a post-synaptically localized G protein-coupled receptor (GPCR) called adhesion GPCR B3 (ADGRB3).

C1QL1 and ADGRB3 likely have pleiotropic functions beyond neuron-neuron synapses. We have recently shown that most C1QL1-expressing cells in the brain co-express the transcription factor OLIG2, indicating that they are of the oligodendrocyte lineage. This suggests that C1QL1-ADGRB3 signaling from glia is associated with remyelination potential. Therefore, we investigated whether C1QL1 has a function in regulating OPC differentiation. We show that C1ql1 is expressed by OPCs, and in most brain regions, is the only cell type expressing C1ql1. To uncover the function of C1QL1, we created OPC-specific conditional knockout (cKO) mice and found that C1ql1 removal from OPCs causes a developmental delay in oligodendrocyte cell density and myelination, but mice recover by adulthood. After mice were challenged by cuprizone-induced demyelination, we found cKO mice had a reduced or delayed oligodendrocyte density and remyelination recovery, while a virus that we designed to overexpress C1QL1 caused an increase in oligodendrocyte density and myelination during recovery.

To study possible mechanistic explanations for these phenotypes, we used primary OPC cultures in vitro and found that C1QL1 levels can bidirectionally regulate the extent of OPC differentiation into oligodendrocytes. Our combined results suggest that C1QL1 signaling may have therapeutic potential for treating demyelinating diseases such as MS.

Salamanders such as the axolotl (Ambystoma mexicanum) are the evolutionarily closest organisms to humans capable of regenerating extensive sections of their body plan, including parts of their eyes, lungs, heart, brain, spinal cord, tail, and limbs throughout their lives, constituting valuable models for regeneration studies. Yet, urodele amphibians are also characterised by an apparent lack of physiological declines through lifespan, indefinite regenerative capacity, extraordinary longevity, and defiance of the Gompertz law of mortality, key features of negligible senescence. Their long lifespans and lack of experimental tractability have historically restricted their use in ageing studies. However, recent technological advances have enabled the axolotl as a tractable model system.

Throughout life, axolotls exhibit several age-defying traits, including dermal thickening, progressive skeletal ossification, and cancer resistance. Further, their tissues do not accumulate senescent cells with age, thereby circumventing a major hallmark of ageing and driver of age-related disorders, in keeping with their proposed negligible senescence status. Yet, whether axolotls exhibit signs of molecular ageing remains unknown.

Changes in the methylation level of cytosines within CpG dinucleotides constitute a primary hallmark of molecular ageing. Indeed, age-related changes in DNA methylation (DNAm) occur across animal species, including mammals, birds, fishes and amphibians. More recently, the Mammalian Methylation Consortium has confirmed that age-related gains in methylation can be observed at target sites of the Polycomb Repressive Complex 2 (PRC2), which catalyses the tri-methylation of lysine 27 on histone H3 (H3K27me3) in all mammalian species. DNA methylation at PRC2 target sites may constitute a universal biomarker of aging and rejuvenation in mammalian systems.

Multivariate regression models based on the methylation status of multiple CpG sites provide accurate age estimators, commonly known as 'epigenetic clocks,' in mammalian species. Initially restricted to humans and mice, the identification of highly conserved CpGs facilitated the construction of multispecies clocks. Here, we conduct DNA methylation profiling of axolotl tissues at CpGs associated with ageing across mammalian and amphibian species. We develop axolotl epigenetic clocks at both pan-tissue and single tissue levels and uncover that axolotls exhibit conserved epigenetic ageing traits during early life but not thereafter, deviating from the established notion of organismal ageing. We reveal that, in contrast to mammals, the axolotl methylome is remarkably stable and does not exhibit substantial shifts at either global or PRC2-associated gene levels late in life.

Senescent cells (SnC) accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating SnC skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period.

Following topical ABT-263, aged skin demonstrated decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-β-gal and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure.

In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.

This paper presents a novel perspective, amassing substantial evidence that targeting NLRP3 not only converges various aging mechanisms but also exerts regulatory control over them. This unique approach underscores a sophisticated interdependence that is yet to be fully understood. Furthermore, NLRP3 appears to regulate cellular senescence so that its activation does not lead to pyroptosis. This suggests that senescent cells could be a persistent source of IL-1β production, thereby contributing to aging. The significance of NLRP3 in aging is highlighted by studies demonstrating that its knockout endows mice with a phenotype of healthspan and lifespan. Additionally, treatments targeting pathways upstream of NLRP3 have been shown to extend the healthspan of primates and reverse various aging symptoms in humans.

Therefore, NLRP3 is not merely a participant in the aging process but potentially acts as a master regulator. Modulating NLRP3 could significantly alter the health trajectories of individuals experiencing NLRP3-mediated accelerated aging. Since this process is largely driven by autologous components, the term 'auto-aging' is proposed. Further research is essential to understand the role of NLRP3 in accelerated aging entirely and to develop healthspan-extending therapies targeting this key regulator.

A critical question remains: Should interventions aim to completely inhibit NLRP3 activation or selectively target specific activation pathways to maximize health benefits? While there appears to be redundancy among NLRs in defending against pathogen-associated molecular patterns, broad inhibition might increase susceptibility to specific infections by weakening primary defense mechanisms. Additionally, better biomarkers are needed to gauge the impact of such therapies on NLRP3 activity. Assessments often focus on free IL-1β levels in plasma, which are minimal due to neutralization by soluble IL receptors. Alternatives could include measuring total IL-1β or utilizing surrogate markers like IL-6 downstream of IL-1β, which may provide a more accurate reflection of NLRP3-mediated inflammatory status.

Huntington's disease (HD) is a hereditary neurodegenerative disorder that manifests with movement disturbances, psychiatric changes, and cognitive decline. It is caused by an unstable CAG repeat expansion in exon1 of the huntingtin gene (HTT), which is translated to an abnormally long polyglutamine (polyQ) stretch in the HTT protein. The expanded polyQ repeats lead to aggregation of mutant HTT and the selective neuronal cell loss in the striatum, cortex, and other brain regions in HD patients.

Under normal conditions, TDP-43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP-43 is mislocalized in the cytoplasm. By investigating HD knock-in mice, we explore whether the pathogenic TDP-43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP-43 without nuclear localization signal. We found that the cytoplasmic TDP-43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior.

Importantly, the cytoplasmic TDP-43, via its binding to the intron1 sequence of the mouse HTT precursor messenger RNA (pre-mRNA), promotes the transport of exon1-intron1 HTT onto the ribosome, resulting in the aberrant generation of exon1 HTT. Our findings suggest that cytoplasmic TDP-43 contributes to HD pathogenesis via its binding to and transport of nuclear un-spliced mRNA to the ribosome for the generation of a toxic protein product.

During aging, miscellaneous changes occur in tissue stem cells. Tissue stem cells often exhibit two opposite phenotypes: proliferation and exhaustion. Proliferation can lead to dysplasia and tumorigenesis. Stem cell exhaustion is often defined as a decline in stem cell numbers and renewal capacity. Although stem cell quiescence and exhaustion share the same property of suppressed proliferation, they are distinct in a sense that quiescent cells, but not exhausted cells, can proliferate upon receiving stresses. Thus, stem cell exhaustion can be defined as a stress-induced cellular status exhibiting decrease of either the cell number or proliferative capacity, which makes stem cells refractory to stimulation and unable to renew upon receiving additional stresses.

Aging-induced stem cell exhaustion occurs in many types of tissue stem cells in mice, including hematopoietic stem cells, intestinal stem cells (ISCs), skeletal muscle stem cells, and hair follicle stem cells. Stem cell exhaustion can occur due to two mechanisms: (1) replicative stress in response to proliferation and (2) mechanisms independent of cell proliferation. The resulting phenotype, proliferation or exhaustion, likely depends on the tug of war competition between conflicting signals. In Drosophila, ISCs demonstrate a proliferative phenotype during aging. Many studies focused on what is driving aging-induced ISC proliferation and elucidated the mechanisms such as JNK signaling, commensal dysbiosis, epithelial barrier disruption, mitochondrial regulation, and an ABC transporter-mediated folate accumulation. Although PIWI was suggested to suppress Jak-Stat-mediated exhaustion of ISCs, signaling that skews ISCs toward exhaustion during aging is not known. There might be some undiscovered signals that lead cells toward exhaustion.

There are many silent changes in chromatin structures and gene expression that are not necessarily reflected in manifested phenotypes during aging. Here through analyses of chromatin accessibility and gene expression in intestinal progenitor cells during aging, we discovered changes of chromatin accessibility and gene expression that have a propensity to exhaust intestinal stem cells (ISCs). During aging, Trithorax-like (Trl) target genes, ced-6 and ci, close their chromatin structures and decrease their expression in intestinal progenitor cells. Inhibition of Trl, ced-6, or ci exhausts ISCs. This study provides new insight into changes of chromatin accessibility and gene expression that have a potential to exhaust ISCs during aging.

The human lifespan is influenced by various factors, with physical activity being a significant contributor. Despite the clear benefit of exercise on health and longevity, the association between different types of sports and lifespan is yet to be considered. Accordingly, we aimed to study this association in a large international cohort of former athletes using a robust linear regression model. We collected data on athletes from public sources, accumulating a total of 95,210 observations, 95.5% of which were accounted for by males. The dataset represented athletes born between 1862 and 2002 from 183 countries across 44 sports disciplines.

We calculated the change in lifespan by measuring the difference in age between athletes and the corresponding reference populations, while accounting for variations caused by sex, year of death, and country. The results revealed that various sports impacted lifespan differently, with male athletes being more likely to experience benefits from sports than female athletes. Among male athletes, pole vaulting and gymnastics were linked to the highest extension in lifespan (8.4 years and 8.2 years respectively), while volleyball and sumo wrestling were the most negatively associated with lifespan (-5.4 years and -9.8 years respectively). The association between lifespan and popular team sports in males was positive for cricket, rowing, baseball, water polo, Australian rules, hurling, lacrosse, field hockey, minimal for rugby, canoeing and kayaking, basketball, gridiron football, and football (soccer), and negative for handball and volleyball. Racquet sports (i.e., tennis and badminton) exhibited a consistent and positive association in both male and female athletes, as shown by an extended lifespan of up to 5.7 years in males and 2.8 years in females.

Although lacking conclusive evidence, we theorize that the observed results may be attributed to the aerobic and anaerobic characteristics of each sport, with mixed sports yielding the maximum benefits for the lifespan. While results from female athletes should be cautiously interpreted, our study highlights the complex interplay between sports and lifespan and contributes to the growing body of knowledge on the multifaceted relationship between physical activity and human longevity.

The accumulation of senescent cells is thought to play a crucial role in aging-associated physiological decline and the pathogenesis of various age-related pathologies. Targeting senescence-associated cell surface molecules through immunotherapy emerges as a promising avenue for the selective removal of these cells. Despite its potential, a thorough characterization of senescence-specific surface proteins remains to be achieved. Our study addresses this gap by conducting an extensive analysis of the cell surface proteome, or "surfaceome", in senescent cells, spanning various senescence induction regimes and encompassing both murine and human cell types.

Utilizing quantitative mass spectrometry, we investigated enriched cell surface proteins across eight distinct models of senescence. Our results uncover significant changes in surfaceome expression profiles during senescence, highlighting extensive modifications in cell mechanics and extracellular matrix remodeling. Our research also reveals substantive heterogeneity of senescence, predominantly influenced by cell type and senescence inducer. A key discovery of our study is the identification of four unique cell surface proteins with extracellular epitopes. These proteins are expressed in senescent cells, absent or present at low levels in their proliferating counterparts, and notably upregulated in tissues from aged mice and an Alzheimer's disease mouse model. These proteins stand out as promising candidates for senotherapeutic targeting, offering potential pathways for the detection and strategic targeting of senescent cell populations in aging and age-related diseases.

Exposure to particulate matter 2.5 (PM2.5) accelerates aging, causing declines in tissue and organ function, and leading to diseases such as cardiovascular, neurodegenerative, and musculoskeletal disorders. PM2.5 is a major environmental pollutant and an exogenous pathogen in air pollution that is now recognized as an accelerator of human aging and a predisposing factor for several age-related diseases.

Approximately 85% of the global population is exposed to air pollution levels above safe limits. Long-term exposure to air pollutants is associated with an increased risk of adverse health outcomes such as dementia, type 2 diabetes, cardiovascular diseases, and lung cancer. Air pollution is now the fourth largest global burden of disease. Therefore, it is imperative to scrutinize the role of air pollution in aging and age-related diseases.

In this paper, we seek to elucidate the mechanisms by which PM2.5 induces cellular senescence, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, and age-related diseases. Our goal is to increase awareness among researchers within the field of the toxicity of environmental pollutants and to advocate for personal and public health initiatives to curb their production and enhance population protection. Through these endeavors, we aim to promote longevity and health in older adults.

Aging is a consequence of complex molecular changes, but whether a single microRNA (miRNA) can drive aging remains unclear. A miRNA known to be upregulated during both normal and premature aging is miR-29. We find miR-29 to also be among the top miRNAs predicted to drive aging-related gene expression changes. We show that partial loss of miR-29 extends the lifespan of Zmpste24-/- mice, an established model of progeria, indicating that miR-29 is functionally important in this accelerated aging model.

To examine whether miR-29 alone is sufficient to promote aging-related phenotypes, we generated mice in which miR-29 can be conditionally overexpressed (miR-29TG). miR-29 overexpression is sufficient to drive many aging-related phenotypes and led to early lethality. Transcriptomic analysis of both young miR-29TG and old wild type mice reveals shared downregulation of genes associated with extracellular matrix organization and fatty acid metabolism, and shared upregulation of genes in pathways linked to inflammation. These results highlight the functional importance of miR-29 in controlling a gene expression program that drives aging-related phenotypes.

Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age.

In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy.

Metformin has been used for more than 60 years to lower blood-sugar levels in people with type 2 diabetes - and is the second most-prescribed medication in the United States. The drug has long been known to have effects beyond treating diabetes, leading researchers to study it against conditions such as cancer, cardiovascular disease, and ageing. Data from worms, rodents, flies and people who have taken the drug for diabetes suggest the drug might have anti-ageing effects. But its effectiveness against ageing had not been tested directly in primates, and it is unclear whether its potential anti-ageing effects are achieved by lowering blood sugar or through a separate mechanism.

This led researchers to test the drug on 12 elderly male cynomolgus macaques (Macaca fasciucularis); another 16 elderly monkeys and 18 young or middle-aged animals served as a control group. Every day, treated monkeys received the standard dose of metformin that is used to control diabetes in humans. The animals took the drug for 40 months, which is equivalent to about 13 years for humans. Over the course of the study, researchers took samples from 79 types of the monkeys' tissues and organs, imaged the animals' brains and performed routine physical examinations. By analysing the cellular activity in the samples, the researchers were able to create a computational model to determine the tissues' 'biological age', which can lag behind or exceed the animals' age in years since birth.

The researchers observed that the drug slowed the biological ageing of many tissues, including from the lung, kidney, liver, skin and the brain's frontal lobe. They also found that it curbed chronic inflammation, a key hallmark of ageing. The study was not intended to see whether the drug extended the animals' lifespans; previous research has not established an impact on lifespan but has shown lengthened healthspan - the number of years an organism lives in good health. The researchers also identified a potential pathway by which the drug protects the brain: it activates a protein called NRF2, which safeguards against cellular damage triggered by injury and inflammation.

Neurocryptococcosis, an infectious disease of central nervous system (CNS) caused by Cryptococcus neoformans (C. Neoformans) and C. gattii, has been observed with increased frequency in aged people, as result of the reactivation of a latent infection or community acquisition. These opportunistic microorganisms belonging to kingdom of fungi are capable of surviving and replicating within macrophages. Typically, cryptococcus is expelled by vomocytosis, a non-lytic expulsive mechanism also promoted by interferon (IFN)-I, or by cell lysis. However, whereas in a first phase cryptococcal vomocytosis leads to a latent asymptomatic infection confined to the lung, an enhancement in vomocytosis, promoted by IFN-I overproduction, can be deleterious, leading the fungus to reach the blood stream and invade the CNS.

Although clinical evidence has pointed out the higher prevalence of neurocryptococcosis in older compared to younger adults, the exact mechanisms underlying this epidemiological evidence still need to be elucidated in depth. However, it is very plausible that age-related disruption of innate and acquired immune response may increase the risk of both cryptococcaemia and neurocryptoccocis and may enhance the direct deleterious effects of cryptococcal infection. Aging-induced defective clearing activity of alveolar macrophages, along with increased polarization into pro-inflammatory M1 cells and increased activation of Th2 responses, are thought to contribute to increased cryptococcal damage. Overall, age-associated alterations in innate immune responses may increase the risk of ineffective cryptococcal clearance, severe pulmonary disease, and dissemination to the CNS.