Fight Aging! Newsletter, December 2nd 2024

Autologous therapy by means of induced pluripotent stem cells (iPSCs) has advantages that include the avoidance of immunological rejection, but it also comes with disadvantages related to the time and expense required for cultivation and the need for tumourigenicity tests. Additionally, from a practical point of view, any instability in the quality of the iPSCs or the graft materials derived from them will lead to the unwanted cancellation of scheduled surgeries. With allogeneic therapy, there is a ready supply of cells, although immunological rejection now becomes an important consideration. However, somewhat unexpectedly, experiments have shown that corneal epithelial cell sheets derived from human iPSCs express lower levels of HLA class I and II compared with somatic cell-derived sheets. Indeed, mixed lymphocyte reaction tests showed no difference in the immune response to iPSC-derived corneal epithelial cell sheets (iCEPSs) between HLA-matched and HLA-mismatched peripheral blood mononuclear cells.

Another important consideration is that the iCEPS construct does not contain immunocompetent cells. It has been reported that a high rate of rejection (about 40%) occurs following an allogeneic corneal limbal transplantation. Previous studies have also indicated that donor-derived Langerhans cells promote early and acute corneal allograft rejection, acting in concert with allogeneic MHC-specific cytotoxic T cells. Graft material for corneal limbal tissue transplantation contains copious antigen-presenting cells, which might increase the probability of a direct pathway to rejection; iCEPSs, however, do not contain immunocompetent cells because only induced corneal epithelial progenitor cells are used to fabricate them. Thus, we hypothesise that HLA compatibility and the use of immunosuppressive agents (above and beyond corticosteroid use) is not necessary for iCEPS transplantation, and incorporate an initial examination of this in our study design. Herein, we report the 52-week follow-up (plus an additional 1-year additional safety monitoring period) of the first-in-human iCEPS transplant surgery in four eyes of four patients with vision loss.

The gut microbiome plays a pivotal role in combating diseases and facilitating healthy aging, and natural products derived from biosynthetic gene clusters (BGCs) of the human microbiome exhibit significant biological activities. However, the natural products of the gut microbiome in long-lived populations remain poorly understood. Here, we integrated six cohorts of long-lived populations, encompassing a total of 1,029 fecal metagenomic samples, and employed the metagenomic single sample assembled BGCs (MSSA-BGCs) analysis pipeline to investigate the natural products and their associated species.

Our findings reveal that the BGC composition of the extremely long-lived group differed significantly from that of younger elderly and young individuals across five cohorts. Terpene and Type I PKS BGCs were enriched in the extremely long-lived, whereas cyclic-lactone-autoinducer BGCs were more prevalent in the young. Association analysis indicated that terpene BGCs were strongly associated with the abundance of Akkermansia muciniphila, which was also more abundant in the long-lived elderly across at least three cohorts.

We assembled 18 A. muciniphila draft genomes using metagenomic data from the extremely long-lived group across six cohorts and discovered that they all harbor two classes of terpene BGCs, which aligns with the 97 complete genomes of A. muciniphila strains retrieved from the NCBI database. The core domains of these two BGC classes are squalene/phytoene synthases involved in the biosynthesis of triterpenes and tetraterpenes. Furthermore, the abundance of fecal A. muciniphila was significantly associated with eight types of triterpenoids. Targeted terpenoid metabolomic analysis revealed that two triterpenoids, Holstinone C and colubrinic acid, were enriched in the A. muciniphila culture solution compared to the medium, thereby confirming the production of triterpenoids by A. muciniphila. The natural products derived from the gut of long-lived populations provide intriguing indications of their potential beneficial roles in regulating health.

The epithelium of the gastrointestinal tract represents the largest mucosal lining in the body that effectively limits the permeation of luminal microorganisms, antigens, and toxins through its paracellular space, a process that is regulated by intercellular tight junctions. Advancing age is accompanied by physiological changes to the intestine, including mucus layer thinning and remodelling of intestinal epithelial tight junction proteins, which contribute towards the breakdown of intestinal barrier function. This permits commensal bacteria and their products, such as lipopolysaccharide, from the gut lumen into the bloodstream (referred to as a leaky gut). Age-related intestinal barrier dysfunction is closely linked to the progressive deterioration of systemic health and the gradual appearance of metabolic defects. Moreover, recent evidence from animal studies indicates that it is a major contributor to low-grade systemic inflammation, termed inflammaging. Human intestinal barrier dysfunction, determined by elevated circulating lipopolysaccharide-binding protein (LBP) levels, is also associated with impaired physical function and inflammaging in healthy aged adults; highlighting the importance of investigating the role of intestinal barrier dysfunction in ageing.

Concurrently with changes to intestinal homeostasis, ageing is accompanied by remodelling of the immune system that attenuates the host's ability to mount robust immune responses, resulting in an immunocompromised state, termed immunesenescence. One of the most striking features of immune ageing is the progressive shrinkage (involution) of the thymus that is characterised by the loss of thymic epithelial cells (TECs), expansion of perivascular spaces, increased thymic adiposity and the accumulation of senescent cells; together resulting in a loss of functional spaces for the development of thymocytes. Collectively this compromises the process of thymopoiesis and result in a reduced thymic output of naïve T cells and the homeostatic expansion of peripheral memory T cell subsets. Further, chronic lifelong antigenic stimulation leads to the accumulation of senescent T cells in the periphery, which impair tissue immunosurveillance and drive a state of prolonged basal inflammation in aged individuals, termed inflammageing.

Despite these interesting findings, the relationship between intestinal barrier dysfunction and immune ageing is poorly understood. Herein we report that intestinal membrane permeability increases with age in humans and is accompanied by enhanced systemic microbial translocation that contributes to the lifelong antigenic burden, driving a reduction in naïve T cell thymic output and an accumulation of terminally differentiated, senescent T cells in the periphery. The emergence of these hallmarks of T cell ageing hinders the ability of these cells to fight invading pathogens and enhances their ability to produce pro-inflammatory cytokines, which ultimately contribute to the inflammatory state of the aged host. Further, we demonstrate that aged germ-free mice, which do not exhibit age-related intestinal barrier dysfunction, are protected from the accumulation of microbial products in the thymus and maintain their thymic architecture. Together, these findings provide novel evidence of a causal relationship between intestinal barrier dysfunction and T cell ageing.

While toxic in high concentrations, copper is essential to life as a trace element. Because cancer cells grow and multiply much more rapidly, they have a significantly higher need for copper ions. Restricting their access to copper ions could be a new therapeutic approach. The problem is that it has so far not been possible to develop drugs that bind copper ions with sufficient affinity to "take them away" from copper-binding biomolecules.

Researchers have now successfully developed such a system. At the heart of their system are the copper-binding domains of the chaperone Atox1. The team attached a component to this peptide that promotes its uptake into tumor cells. An additional component ensures that the individual peptide molecules aggregate into nanofibers once they are inside the tumor cells. In this form, the fiber surfaces have many copper-binding sites in the right spatial orientation to be able to grasp copper ions from three sides with thiol groups (chelate complex). The affinity of these nanofibers for copper is so high that they also grab onto copper ions in the presence of copper-binding biomolecules. This drains the copper pools in the cells and deactivates the biomolecules that require copper. As a consequence, the redox equilibrium of the tumor cell is disturbed, leading to an increase in oxidative stress, which kills the tumor cell.

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu+ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu+ homeostasis in cancer cells are rarely explored because small molecule Cu+ chelators have poor binding affinity in comparison to the intracellular Cu+ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu+ chaperone-inspired supramolecular approach to disrupt Cu+ homeostasis in cancer cells that induces programmed cell death.

The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu+ due to the presence of the unique MTCGGC motif, which is conserved in intracellular Cu+ chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells, impairs the activity of Cu+ dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu+ binding must work in synergy to successfully disrupt Cu+ homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis.

The gut microbiome plays a significant role in longevity, and dysbiosis is indeed one of the hallmarks of aging. However, the causal relationship between gut microbiota and human longevity or aging remains elusive. Our study assessed the causal relationships between gut microbiome and longevity using Mendelian Randomization (MR). Summary statistics for the gut microbiome were obtained from four genome-wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340), Dutch Microbiome Project (N = 7738), German individuals (N = 8956), and Finland individuals (N = 5959). Summary statistics for Longevity were obtained from five GWAS meta-analysis, including Human healthspan (N = 300,447), Longevity (N = 36,745), Lifespans (N = 1,012,240), Parental longevity (N = 389,166), and Frailty (one of the primary aging-linked physiological hallmarks, N = 175,226).

Our findings reveal several noteworthy associations, including a negative correlation between Bacteroides massiliensis and longevity, whereas the genus Subdoligranulum and Alistipes, as well as species Alistipes senegalensis and Alistipes shahii, exhibited positive associations with specific longevity traits. Moreover, the microbial pathway of coenzyme A biosynthesis I, pyruvate fermentation to acetate and lactate II, and pentose phosphate pathway exhibited positive associations with two or more traits linked to longevity. Conversely, the TCA cycle VIII (helicobacter) pathway consistently demonstrated a negative correlation with lifespan and parental longevity. Our findings of this MR study indicated many significant associations between gut microbiome and longevity. These microbial taxa and pathways may potentially play a protective role in promoting longevity or have a suppressive effect on lifespan.

Dry eye disease (DED) is one of the most common ocular surface diseases affecting the quality of life of the elderly population, and aging is also one of the independent risk factors for DED. The lacrimal gland is an exocrine gland that contributes mainly to the aqueous component of the tear film, and its secretion constitutes the majority of the tear film (98% to 99%). It consists of three main cell types: acinar epithelial cells, ductal epithelial cells, and myoepithelial cells. The most abundant type (about 80%), the acinar epithelial cells are highly polarized epithelial cells responsible for the synthesis and secretion of aqueous fluid.

The lacrimal gland is highly susceptible to the effects of aging, which manifests as structural and functional damage, with major pathological changes, including acinar epithelial cells atrophy, periductal fibrosis, and chronic inflammatory cells infiltration, as well as a decrease in the density of nerves driving lacrimal secretion, which ultimately leads to qualitative and quantitative abnormalities in lacrimal gland secretions.

In this study, we discovered that aging increased oxidative stress, which increased apoptosis, and generated reactive oxygen species (ROS) in acinar epithelial cells. Furthermore, activation of PINK1/Parkin-mediated mitophagy by rapamycin reduced lacrimal gland ROS concentrations and prevented aging-induced apoptosis of acinar cells, thereby causing histological alterations, microstructural degradation, and increasing tear secretion associated with ROS accumulation. Overall, our findings suggested that aging could impair mitochondrial function of acinar cells, and age-related alterations may be treated with therapeutic approaches that enhance mitophagy while maintaining mitochondrial function.

The possibility to detect misfolded α-synuclein (α-syn) in different tissues and body fluids is currently revolutionizing the diagnosis of Parkinson's disease (PD) and it is hoped that a more secure and much earlier diagnosis will soon be possible. In this context one of the most promising advances is the use of α-syn seed amplification assays (SAA), utilizing the seeding activity of pathological α-syn conformers to introduce aggregation of recombinant α-syn.

We recently demonstrated that a SAA for the detection of pathological α-syn in neuronal-derived extracellular vesicles (NEs) purified from blood, distinguishes PD patients from healthy controls with high sensitivity. This study set out to 1) confirm the previously reported high sensitivity of this blood-based SAA in a larger cohort of individuals with PD and 2) additionally explore changes of α-synuclein seeding in blood in the course of PD.

In the cross-sectional dataset, 79 of 80 PD patients (mean age 69 years; 56% male) and none of the healthy controls (n = 20, mean age 70 years; 55% male) showed seeding activity (sensitivity 98.8%). When comparing subgroups divided by disease duration, longer disease duration was associated with lower α-synuclein seeding activity. In the longitudinal analysis 10/11 patients showed a gradual decrease of α-synuclein seeding activity over time. This study cannot explain the pathophysiological processes behind this observed decrease. However, it can be hypothesized that spreading of α-syn is more pronounced in the early stages of the disease.

Aging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits.

Proteins are effective biotherapeutics and have several advantages over gene therapy, especially for prolonged treatments. In the present study, we investigated the possibility that the LAV-BPIFB4 protein protects cardiac health in older and obese mice with type 2 diabetes. Results show that LAV-BPIFB4 therapy can benefit both conditions, indicating that this longevity-associated protein can antagonize two prevalent risk factors for heart failure. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females.

Brain age is a machine learning-derived estimate that captures lower brain volume. Previous studies have found that brain age is significantly higher in mild cognitive impairment and Alzheimer's disease (AD) compared to healthy controls. We utilized data from an archival dataset, mainly Alzheimer's disease Neuroimaging Initiative (ADNI). We included control participants (healthy controls or HC), individuals with mild cognitive impairment (MCI), and individuals with Alzheimer's disease (AD). We conducted longitudinal modeling of age and brain age by group using time from baseline in one model and chronological age in another model.

We predicted brain age with a mean absolute error (MAE) of less than 5 years. Brain age was associated with age across the study and individuals with MCI and AD had greater brain age on average. We found that the MCI group had significantly higher rates of change in brain age over time compared to the HC group regardless of individual chronologic age, while the AD group did not differ in rate of brain age change. We essentially found that while the MCI group was actively experiencing faster rates of brain aging, the AD group may have already experienced this acceleration (as they show higher brain age). AD may represent a homeostatic endpoint after significant neurodegeneration. Future work may focus on individuals with MCI as one potential therapeutic option is to alter rates of brain aging, which ultimately may slow cognitive decline in the long-term.

The prevalence of coronary artery disease (CAD) is higher in men than in women, but the underlying molecular basis for this sexual dimorphism are poorly understood. There is a consensus on the protective role of estrogens and CAD risk increasing following menopause. Likewise, men develop lipid-rich plaques, whereas women are more likely to develop fibrous plaques with a unique transcriptomic and proteomic signatures in the plaque. Otherwise, presentation of oxidative stress and inflammation may differ between women and men but are inconsistent.

In healthy humans, aging is associated with a progressive endothelium-dependent dilatory decline, which appears 10 years earlier in men than in women and is highly predictive of future cardiovascular events. In recent years, research has established that age-related accumulation of senescent cells could cause chronic low-grade cold inflammation, also known as inflammaging, through the release of the senescence-associated secretory phenotype (SASP). Because SASP involves a range of proinflammatory factors with important paracrine and autocrine effects on cell and tissue biology, inflammaging could promote cardiovascular disease (CVD).

We prospectively collected distal segments of lesion-free internal thoracic arteries during coronary artery bypass graft surgeries from both men and women. Our data show that endothelial dysfunction is more pronounced in men compared to women. Importantly, using single-nuclei transcriptomics, senescent and inflammatory transcriptomic signatures suggestive of the inflammaging were only identified in male endothelial cells, not in female endothelial cells. Therefore, senescence-associated endothelial dysfunction may contribute to atherogenesis in men.

Cardiometabolic diseases (CMDs) have emerged as the most significant health challenges. Cardiometabolic multimorbidity (CMM) refers to the coexistence of two or more CMDs, including conditions such as stroke, ischemic heart disease (IHD), and type 2 diabetes (T2D). Populations with CMM have a two-fold increased mortality risk and a 12-15 year reduced life expectancy than those with single CMDs. Biological aging, which is associated with decreased metabolic rates, vascular stiffening, chronic inflammation, and oxidative stress, as well as the interplay of comorbidities, may underlie the progression of CMDs to CMM.

The ideal measurement strategy for biological aging should include as many system indicators as possible. For predicting disease, the PhenoAge and Klemera-Doubal method Biological Age (KDM-BA) are the best-validated algorithms according to blood-chemistry-derived measures in multi-ethnic cohorts of older adults. Accelerated aging refers to the phenomenon where an individual's biological age advances more rapidly than their chronological age. This concept goes beyond the mere passage of time, as it emphasizes the underlying biological processes and pathological changes. Thus, this study used both algorithms to test the association between biological aging and CMM.

The study included 415,147 individuals with an average age of 56.5 years. During the average 11-year follow-up period, CMD-free individuals with accelerated aging had a significantly greater risk of CMD (KDM-BA, hazard ratio [HR] 1.456; PhenoAge, HR 1.404), CMM (KDM-BA, HR 1.952; PhenoAge, HR 1.738), dementia (KDM-BA, HR 1.243; PhenoAge, HR 1.212), and mortality (KDM-BA, HR 1.821; PhenoAge, HR 2.047) in fully-adjusted Cox regression models. Accelerated aging had adjusted HRs of 1.489 (KDM-BA) and 1.488 (PhenoAge) for CMM, 1.434 (KDM-BA) and 1.514 (PhenoAge) for dementia, and 1.943 (KDM-BA) and 2.239 (PhenoAge) for mortality in participants with CMD at baseline.

This meta-analysis investigated the differences in working memory (WM) performance between athletes and non-athletes in non-sports-specific tasks. A comprehensive evaluation of 21 studies encompassing different age groups, genders, and sports types identified a small but statistically significant advantage in WM accuracy or capacity for athletes compared to non-athletes. Notably, this advantage was more pronounced when athletes were contrasted with a sedentary population.

We conducted seven subgroup analyses as part of this study. An age-specific investigation revealed a small but significant advantage in WM for young adult athletes over non-athletes. However, our investigation into the link between sports expertise and WM across various age groups is limited by a lack of substantial research focusing on older adults and children. Therefore, we are unable to confirm whether older athletes exhibit superior WM enhancement in comparison to other demographic groups. Considering the benefits of exercise for mitigating age-related cognitive decline, as well as its role in improving cognitive and learning abilities during childhood and adolescence, studies focusing on these age groups would be important. In particular, studies on older adults who are ex-athletes could provide insights into the long-term effects of sports.

Subgroup analysis based on sports types revealed that athletes from individual sports outperformed non-athletes in experimental WM tasks, while athletes from team sports showed no such significant advantage. Contrary to our expectations, no significant difference was found between individual and team sports subgroups in WM performance. These results suggest that the cognitive gains afforded by engaging in sports likely arise from general physiological and psychological effects.

Our comparison of WM performance of elite and non-elite athletes with that of non-athletes identified a WM advantage for elite athletes, while the advantage for non-elite athletes approached but did not reach statistical significance. Additionally, there was no significant difference in WM performance between the two subgroups. This finding prompts introspection regarding the sports performance-cognition nexus. Our results imply that cognitive benefits, particularly with respect to WM, stem more from sustained engagement in workout than from the high competitive level achieved.

The WM advantage observed in athletes in comparison to non-athletes is likely based on both physiological and psychological mechanisms. Physiologically, sports confer efficiency advantages in information processing and cognitive function by increasing cerebral blood flow, triggering the release of brain-derived neurotrophic factor, and promoting neural network plasticity. Psychologically, sports confer benefits that optimise cognitive performance through improved control, enhanced attention allocation, and accelerated information processing.

Aging is the leading driver of disease in humans and has profound impacts on mortality. Biological clocks are used to measure the aging process in the hopes of identifying possible interventions. Biological clocks may be categorized as phenotypic or epigenetic, where phenotypic clocks use easily measurable clinical biomarkers and epigenetic clocks use cellular methylation data. In recent years, methylation clocks have attained phenomenal performance when predicting chronological age and have been linked to various age-related diseases. Additionally, phenotypic clocks have been proven to be able to predict mortality better than chronological age, providing intracellular insights into the aging process.

This review aimed to systematically survey all proposed epigenetic and phenotypic clocks to date, excluding mitotic clocks (i.e., cancer risk clocks) and those that were modeled using non-human samples. We reported the predictive performance of 33 clocks and outlined the statistical or machine learning techniques used. We also reported the most influential clinical measurements used in the included phenotypic clocks. Our findings provide a systematic reporting of the last decade of biological clock research and indicate possible avenues for future research.

Researchers have spent years identifying what are claimed to be methodological errors throughout the longevity literature. For Blue Zones, the main argument is that a significant proportion of supposed centenarians may simply not exist. Around 1900, when the U.S. started to issue birth certificates, the number of centenarians aged 110 or older dropped sharply - presumably because people had been misrecording their age, whether on purpose or accidentally. Similarly, after the Greek government began checking on people receiving pensions, about 70% of all alleged centenarians in the country turned out to be dead. Researches also found that some age databases contain unusual numbers of people born on the first day of the month or on dates divisible by five, suggesting many of these birth dates are fabricated.

It is no coincidence that blue zones are found in poor, remote places that may have spotty record keeping. One can further argue that the supposed healthy lifestyle of the people who live in blue zones is not always backed up by real world data. For example, out of 47 Japanese prefectures, Okinawa ranks first on body mass index, second on beer consumption, and fourth on suicide rate among people over the age of 65.

"If equivalent rates of fake data were discovered in any other field - for example, if 82% of people in the UK Biobank or 17% of galaxies detected by the Hubble telescope were revealed to be imaginary - a major scandal would ensue. In demography, however, such revelations seem to barely merit citation. What demographers call validation is actually just checking the consistency of documents. If documents are consistently wrong then errors are not detectable."

Ageing is a major risk factor that contributes to increased mortality and morbidity rates during influenza A virus (IAV) infections. Macrophages are crucial players in the defense against viral infections and display impaired function during ageing. However, the impact of ageing on macrophage function in response to an IAV infection remains unclear and offers potential insight for underlying mechanisms. In this study, we investigated the immune response of young and aged human monocyte-derived macrophages to two different H1N1 IAV strains.

Interestingly, macrophages of aged individuals showed a lower interferon response to IAV infection, resulting in increased viral load. Transcriptomic data revealed a reduced expression of stimulator of interferon genes (STING) in aged macrophages albeit the cGAS-STING pathway was upregulated. Our data clearly indicate the importance of STING signaling for interferon production. Evaluation of mitochondrial function during IAV infection revealed the release of mitochondrial DNA to be the activator of cGAS-STING pathway. The subsequent induction of apoptosis was attenuated in aged macrophages due to decreased STING signaling.

Our study provides new insights into molecular mechanisms underlying age-related immune impairment. To our best knowledge, we are the first to discover an age-dependent difference in gene expression of STING on a transcriptional level in human monocyte-derived macrophages possibly leading to a diminished interferon production.