Loss-of-function mutations in ABCA1 cause Tangier disease. The phenotype of their markedly reduced or loss of blood high-density lipoprotein (HDL) cholesterol, as well as examination of ATP-binding cassette transporter A1 (ABCA1)-deficient mice, proved that ABCA1 is a key player in HDL production. The ABCA1-mediated cholesterol efflux is the first step in the reverse cholesterol transport system and understanding the regulation of its expression was expected to lead to the development of anti-atherosclerotic drugs. However, from the viewpoint of intracellular cholesterol homeostasis, it is difficult to say that simple activation of ABCA1 or promotion of cholesterol efflux is a good strategy.

This review discusses the possibilities and limitations of strategies to increase HDL, activate cholesterol efflux, and enhance ABCA1 expression, centered on the strict regulatory mechanisms of intracellular cholesterol. Since the benefits of increasing blood levels of HDL-C, once called "good cholesterol," have been doubted, attention has turned to cholesterol efflux enhancement and ABCA1 activation as the next "good" thing. However, there is no evidence that HDL-increasing drugs by enhancing ABCA1 expression prevent atherosclerotic cardiovascular disease in humans.

Essentially, HDL, cholesterol efflux, and ABCA1, may be systems for transporting lipophilic "poisons" including cholesterol to the liver which is the main detoxification organ. In particular, ABCA1 has been reported to not only excrete cholesterol and phospholipids, but also to temporarily reserve the outer leaflet of the plasma membrane and to flop excess cholesterol from the inner to the outer leaflet of the plasma membrane. As these findings show, the organism has a very sophisticated system, so a rough treatment that simply increases blood HDL-C levels, cholesterol efflux, or ABCA1 expression is not likely to be successful. On the other hand, in situations where intracellular cholesterol homeostasis is disrupted by inflammation, aging, or metabolic abnormalities, a strategy that restores reduced ABCA1 expression and cholesterol efflux in a timely and localized manner may be useful.

Like so much in our modern world, curing the diseases of aging is a collaborative effort. In 2021, SENS Research Foundation (SRF) found itself at the center of a brand new way to fundraise. The ingenuity and generosity of Richard Heart, and the willingness to envision a life free from age-related disease from a forward-thinking global community, provided SRF with unprecedented resources. We gained not only in funding, but also in number of supporters. Our vision struck a chord that reverberated across a broader group of people than ever before. Our mission inspired so many to put their trust and resources behind us, and we could not be more grateful or more determined to honor their support through the acceleration and expansion of our vital research. At the same time, we had a changing of the guard at SRF. Undergoing internal investigations in the public eye, under intense scrutiny. Saying goodbye to our visionary founder, to a full half of our Board of Directors, and to our long-time Director of Education.

Within the last year, SRF has seen more upheaval, more incredible support, and more intense criticism, than in the entirety of the previous decade. And yet we remain, passionately in pursuit of the mission that drove our founding. Our dedication to making the 'Strategies for Engineered Negligible Senescence' a life-saving reality is rock-solid, as we hope this Annual Report will make clear. Our mission is vital; one hundred thousand people die every day of age-related disease. Millions more suffer due to age- related decline and disability. Our mission cannot be side-tracked, cannot be delayed, and must take precedence over all other concerns. Last year was difficult, but also empowering. Our leadership may change, but our founding vision is powerful and keeps us focused on the path ahead. Our mission is our defining priority. Together, we will build this new world, one brick at a time.

Catalytic Antibodies Targeting Intracellular Tau Oligomers

Therapeutic interventions with anti-tau immunotherapies have shown promise, but the efficacy seems to vary greatly. The tau LysoSENS group at SENS Research Foundation is investigating the therapeutic potential of catabodies (catalytic antibodies) targeted to the intracellular compartment to degrade tau aggregates and prevent or reverse tau-associated neurodegeneration. Unlike conventional binding antibodies, catabodies bind transiently to their targets and hydrolyze them into very small hydrolytic end-products, leaving the catabody free to attack the next target molecule.

Rejuvenating Immune Surveillance of Senescent Cells

Natural Killer (NK) cells are a known key immune cell type responsible for the immune-mediated senolysis of senescent cells. Moreover, NK cells are increasingly emerging as an important defense against several age-related diseases, the best-understood example of which is cancer. However, NK cell function declines as part of immunosenescence, and this likely includes immune surveillance of senescent cells, leaving the host increasingly vulnerable to diseases of aging, as recently reviewed in a paper published by the Sharma lab at SENS Research Foundation.

To understand the potential of NK cell transplantation as an immunosenolytic therapy, the ApoptoSENS team is collaborating with the Campisi lab at the Buck Institute to investigate the effect of aging on NK cell cytotoxicity toward senescent cells. Studies will test the ability of young vs. old donor derived NK cells to remove senescent cells in a mouse model. Additionally, the Sharma lab is in the process of developing CAR (Chimeric Antigen Receptor)-NK cells with enhanced ability to target senescent cells for adoptive cell therapy, and the above studies will be repeated using CAR-NK cells.

Studying age-related changes in the immune cells has led the ApoptoSENS team to discover a sub-population of T-cells that declines with age. Analysis indicates that these "X cells" constitute only approximately 5% of total peripheral blood mononuclear cells, so in order to investigate their interaction with senescent cells, the team established a protocol for enrichment of X cells in culture. These experiments indicated that X cells rapidly kill senescent cells. Based on these promising initial results, Sharma and coworkers are now further assessing the therapeutic potential of this sub- population of T cells, as they appear to be highly selective in eliminating senescent cells in a substantially shorter time than has been reported by others or observed in their own prior work with NK cells.

Engineering New Mitochondrial Genes to Restore Mitochondrial Function

The MitoSENS lab at SENS Research Foundation, led by Dr. Amutha Boominathan, is working to develop rejuvenation biotechnologies to repair or obviate the accumulation of mitochondrial DNA (mtDNA) mutations with age. Their principal focus is allotopic expression (AE), in which copies of the protein-encoding mtDNA genes are placed in the nucleus, with suitable modifications to allow them to be expressed in the nucleus and translated in the cytosol, following which they must be imported into the mitochondria. There, these gene copies can incorporate into the relevant electron transport chain complexes and contribute to sustaining oxidative phosphorylation. This would allow mitochondria to continue producing ATP, irrespective of the accumulation of particular mtDNA mutations.

Boominathan and colleagues implemented that strategy in the past to synthesize 2 versions of the 13 mtDNA genes: a) the minimally recoded version that is absolutely required for productive protein translation in the cytosol and b) the codon-optimized version, synchronizing the codon usage in these genes to the mammalian nuclear code. They were able to successfully demonstrate robust transient protein production and mitochondrial association for all the 13 mtDNA genes using the codon-optimized gene expression constructs. Cytosolic protein expression under transient expression was substantially higher for the codon-optimized than for minimally-recoded genes, and similarly for steady-state mRNA levels under stable selection. Eight of the re-engineered genes retained expression and targeting to the organelle after stable selection. Building on these early observations, the team validated the utility of these codon-optimized mtDNA gene constructs for additional mitochondrial protein targets that did not work in the past.

The mitochondrial DNA deletions that accumulate in aging cells have a strong selection advantage, amplifying within post-mitotic cells to the point of homoplasmy. The MitoSENS team is exploring a strategy to address this issue by transferring exogenous, viable mitochondria modified for sustained retention and for therapeutic activity. While mitochondrial transplantation is already being investigated by several groups and companies as a therapeutic intervention strategy, Dr. Boominathan's team is advancing an improvement on this strategy using mitochondria with genomes engineered for dominance over the native genotype.

Target Prioritization of Extracellular Matrix Aging

As we age, changes occur not only in the cells within the extracellular matrix (ECM), but importantly also in the composition and chemistry of the ECM. Many of the characteristic physical changes that we associate with ageing, such as the changes in skin appearance or the decrease in flexibility of joints, are specifically the result of changes in the structure and composition of the ECM. Two important components of the ECM are elastin and collagen; indeed, collagen is estimated to account for about 30% of the protein in the body. The Clarke lab is investigating age-related changes in the chemical structure of elastin and collagen and how these changes impact the mechanical behavior of the tissues.

Prior to Clark's investigations, the general consensus in the literature was that tendon increases in stiffness with age and that this was due to an increase in crosslinking between collagen molecules. His group has instead found was that it is not possible to say that tendon gets stiffer with age, particularly when comparing mature to genuinely aged animal tissue. Instead, Clark and colleagues report an increase in the breaking strain, a decrease in the ability to absorb stress, and an increase in the fragility (chance of rupture) with age. This is clearly a more refined and complex description of the physical properties, and accords better with the orthopedic vulnerabilities of aging human tissues.

Clarke's research has also revealed an increase in irreversible crosslinks in the tendon with age, which increase the force required to break a tendon. This increase occurs even as the tendon gradually becomes depleted of reversible crosslinks that allow the tendon to adapt to and absorb force. Understanding how each of these different crosslinks affect the mechanical properties of a tissue and how they change in number with age will enable more targeted strategies for rejuvenation biotechnologies. Based their findings, Clarke and colleagues predict that to rejuvenate youthful tendon function would entail decreasing the number of irreversible crosslinks while greatly increasing the reversible crosslinks. Conceptually, this could be achieved through various means, some of which might not involve directly targeting the crosslinks themselves, but instead cell therapy or other approaches that rejuvenate the behavior of the cells that turn over the ECM. In principle, an unbalanced approach based exclusively on breaking a subset of crosslinks might improve some aspects of tissue function but also cause structural problems.

Lipofuscin Degradation by Bacterial Hydrolases

According to the "garbage catastrophe theory of aging", the accumulation of lipofuscin aggregates limits the remaining life span of the organism by disturbing lysosomal function and inducing cell death. While humans have no enzymes capable of breaking down lipofuscin, microorganisms possess a wide array of enzymes that allow the degradation of any conceivable molecule formed in nature. Thus, the LysoSENS strategy seeks to identify microbes that are able to degrade lipofuscin via specific hydrolases as lead candidates for potential longevity therapeutics. To pursue this goal, the Grune lab will use authentic lipofuscin derived from human cardiac tissue.

Dr. Grune and colleagues extracted microorganisms from different soil samples collected at a residential yard, a forest, a compost heap, and a riverbed. The team used these extracts to select lipofuscin-degrading bacteria by growing cultures on isolated lipofuscin as the only energy, carbon, and sulphur source. Following 20 sets of sub-culture passaging, bacterial mixtures growing on human tissue-derived lipofuscin were extracted, and 12 bacterial strains were isolated. These strains and their specific enzymes will be isolated and further investigated. It bears noting that it is not expected that these bacterial enzymes will prove to be proteases, but hydrolases able to degrade complex crosslinks between proteins. This fact will complicate the identification of lead candidates, but on the other hand, such structures will be unique to lipofuscin and able to function in mammalian cells (after suitable modification) without the danger of digesting functional proteins. A future task will be the targeting of the identified hydrolases towards the lysosomal compartment.

SenoStem: Combinatorial Rejuvenation Biotechnologies

Age-related disease and disability results from the complex interaction of multiple forms of cellular and molecular aging damage. Prominent examples of this damage are the loss of stem cells and the accumulation of senescent cells. Senescent cells propagate damage and impose systemic metabolic derangement through the secretion of a senescence-associated secretory profile (SASP). The SenoStem project at SENS Research Foundation is testing the hypothesis that combination therapy using senolytics and stem cell transplantation will have a synergistic beneficial effect on aging mice and might be able to further improve health and lifespan - literally a remove-and-replace strategy. This approach builds toward SRF's larger long-term goal to develop synergistic combinatorial rejuvenation biotechnology approaches.

Microglia as a Vehicle for Brain Rejuvenation

With SRF funding, the Hébert team has developed a protocol for using microglia as a delivery system for biologics over wide areas of the adult brain. With this protocol, endogenous microglia are replaced with transplanted microglia after a single superficial cell injection. Microglia are migratorily more active compared to neuronal progenitors and more easily spread throughout the brain. In addition to therapeutic proteins, this system can be used to deliver new neurons to all areas of the brain to counteract neuronal loss with age. The transplanted microglia can be engineered to produce a secreted biologic, or engineered to be reprogrammed to new neurons. In both cases, normal microglia density is innately re-established, minimizing any effect of transient microglia depletion while providing novel therapeutic support to brain function.

Identification and Targeting of Noncanonical Death Resistant Cells

It is well established that senescent cells (SCs) can result from a number of stressors, including replicative stress, telomere erosion and damage, and oncogene expression. They are also induced as part of tissue remodeling in wound healing and development. More recently, it was discovered that SCs can spread the senescent phenotype to other cells in the body. Characterization of secondary SCs and differentiating their biology and vulnerabilities from those of primary SCs is thus critical to developing longevity therapeutics targeting the full spectrum of senescence in aging, and is the central focus of Dr. Admasu's work at SENS Research Foundation. With his SRF colleagues, Dr. Adamasu developed a novel protocol to overcome one major roadblock in this endeavor, which has allowed him to make new insights into secondary senescence and identify a highly significant therapeutic target for senolytic drugs with broad senolytic activity against both primary and secondary SCs.

Senescence exerts multiple and sometimes opposing effects in tumorigenesis. The oncogenic activation events involved in cancer initiation trigger oncogene-induced senescence (OIS) in preneoplastic lesions and limit their progression. Consequently, mutations that disable senescence are needed for tumours to progress to more malignant stages. Most cancer therapies work, at least in part, by triggering senescence (therapy-induced senescence, TIS). But TIS in non-cancerous cells has been linked to some of the side effects associated with chemotherapy. And lingering senescent cells present in the tumour and TME contribute to sustain cancer development and progression.

Different types of senescent cells are present in the tumour microenvironment (TME) during cancer initiation, progression and in response to therapy. Many preneoplastic lesions are enriched in senescent cells. This is because activation of oncogenes (e.g., RAS in lung or BRAF in nevi) or loss of tumour suppressor (e.g., PTEN in the prostate) induces senescence, what restrains tumour progression. Another contributor to senescence-induction in the context of tumorigenesis are anti-cancer treatments, as radiotherapy, conventional chemotherapy and some targeted therapies: that cause so-called therapy-induced senescence (TIS) in the tumour cells. Cancer therapies can also induce senescence in cells other than the tumour cells. Indeed, induction of senescence in normal tissues has been suggested to cause some of the side effects associated with chemotherapy.

Finally, other cells in the TME might also undergo senescence. Stromal senescent cells are an emerging factor contributing to tumorigenesis and promote cancer drug resistance. Senescent cells in the TME can also arise in a paracrine fashion, as factors secreted by tumour (senescent) cells can induce senescence in the stroma or render infiltrating immune cells senescent. For example, a study using a p16INK4A luciferase reporter mice show how after implanting different tumour cells grafts that do not express the luciferase reporter, luciferase activity arises in the tumour-associated stroma, demonstrating the ability of tumours to induce senescence in their surroundings.

In this review, we enumerate how current anti-cancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. While senescent cells influence many aspects of tumour progression, a way to deploy senotherapeutics for cancer treatment is the so-called "one-two punch" approach. The rationale of "one-two punch" therapies is that many cancer therapies induce senescence and using senolytics (as a second punch) would therefore target a newly exposed vulnerability in the cancer cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment.

One-two punch protocols have been tried with a wide range of senolytics, including cardiac glycosides, BRD4 inhibitors, and galacto-coated nanoparticles loaded with doxorubicin or navitoclax or the Gal-Nav prodrug. There are several clinical trials evaluating the effect of the senolytic navitoclax in combination with chemotherapy in cancer patients. However, the contribution of senescence and senolysis to the therapeutic effect will not be evaluated on most of those trials. In addition, other senolytics, such as the dasatinib and quercetin combination or fisetin, are being evaluated in different trails, including one aiming to improve frailty in adult survivors of childhood cancer.

In addition to clinical trials, retrospective analysis is another way to test the potential of drugs repurposed as senolytics. For example, cancer patients treated with the cardiac glycoside digoxin during chemotherapy have a better overall survival. Cardiac glycosides have pleiotropic effects, and the aforementioned study attributed the effect to immunogenic cell death. But given that cardiac glycosides have senolytic properties, it would be worthy investigating whether senolysis might explain those results.

Last fall, a group of 30 people gathered at an Etobicoke estate to sample the latest in life-extension innovations. They sipped brain-boosting beverages laced with lion's mane mushrooms and garnished with grapefruit, participated in a breathwork session and soaked up the electromagnetic pulses of the BioCharger, a 20,000 device that looks like a giant blender, sounds like a bionic mosquito and is purported to fight chronic disease, brain fog, and flagging libido, among many other ailments. The evening was a soft launch for Longevity House, a private members' club for Toronto's burgeoning community of biohackers.

The price tag, 100,000 for a lifetime membership, was staggering. The promise, even more so: a chance to live longer, possibly to 120 years old. And not just longer but better, free from chronic illness and cognitive decline, by which standard six figures starts to sound like a bargain. Before launching Longevity House, Michael Nguyen was best known as the haberdasher to Toronto's one-percenters. In 2021, Nguyen purchased a 3-million, 7,500-square-foot mansion in Mimico and packed it with the latest in high-performance fitness equipment: alongside the BioCharger is a Tonal (the weightlifting system LeBron James uses), a Carol (an artificially intelligent exercise bike) and a Katalyst (an electronic muscle-stimulation garment that looks like a wetsuit and promises "the world's most efficient workout"). There is also a red-light therapy room, a full-body vibration plate, a cold plunge tub, and a custom-built sauna. Nguyen and his team have secured partner-ships with in-demand health and wellness-practitioners-naturopaths, breathwork specialists, a chakra guy, a therapist who specializes in psychedelics, and functional-medicine doctors who read blood and stool samples like physiological tea leaves.

Biohacking - to "hack" one's biology for the purposes of optimization - is wellness spiked with gadgetry. It's New Age woo-woo with internet-age efficiency, Gwyneth Paltrow's Goop but for tech bros. (As yet, Longevity House has no female members, and on more than one occasion, I heard Joe Rogan's name spoken with reverence.) What is a biohack, exactly? That's hard to pin down since the category covers pretty much any health intervention, from the obvious to the outlandish. Yoga is a biohack. So is wearing a Fitbit. So are probiotics and mood-enhancing supplements, forest bathing, and looking deeply into another person's eyes for a full minute. Also DIY experimental gene editing, fecal transplantation, and uploading your consciousness onto an external server in the hopes of one day joining a race of cyborgs. (Elon Musk is working on it.) The common thread among biohackers is a mindset that views Mother Nature's work as a starting point.

Nguyen is used to the naysayers - history is littered with them. "We're operating outside the norms of society, which can make people nervous," he says. And that's true, isn't it? Don't all breakthroughs start off as someone's outlandish idea? Wasn't Galileo convicted of heresy for his audacious insistence that the Earth orbits the sun? Isn't it possible that my staunch allegiance to science will leave me on my deathbed while the biohackers skateboard into the next century? Nguyen is a charming and passionate hype man. But is he a modern Galileo or just a guy cashing in on the latest craze?

Age-associated changes in T-cell function play a central role in immunosenescence. The role of aging in the decreased T-cell repertoire, primarily because of thymic involution, has been extensively studied. However, increasing evidence indicates that aging also modulates the mechanical properties of cells and the internal ordering of diverse cell components. Cellular functions are generally dictated by the biophysical phenotype of cells, which itself is also tightly regulated at the molecular level. Based on previous evidence suggesting that the relative nuclear size contributes to variations of T-cell stiffness, here we examined whether age-associated changes in T-cell migration are dictated by biophysical parameters, in part through nuclear cytoskeleton organization and cell deformability.

In this study, we first performed longitudinal analyses of a repertoire of 111 functional, biophysical, and biomolecular features of the nucleus and cytoskeleton of mice CD4+ and CD8+ T cells, in both naive and memory state. Focusing on the pairwise correlations, we found that age-related changes in nuclear architecture and internal ordering were correlated with T-cell stiffening and declined interstitial migration. A similarity analysis confirmed that cell-to-cell variation was a direct result of the aging process and we applied regression models to identify biomarkers that can accurately estimate individuals' age. Finally, we propose a biophysical model for a comprehensive understanding of the results: aging involves an evolution of the relative nuclear size, in part through DNA-hypomethylation and nuclear lamin B1, which implies an increased cell stiffness, thus inducing a decline in cell migration.

Researchers examined data on exercise and the brain for 2,550 participants of the Rhineland Study. "We were able to show that physical activity had a noticeable effect on almost all brain regions investigated. Generally, we can say that the higher and more intense the physical activity, the larger the brain regions were, either with regard to volume or cortical thickness. In particular, we observed this in the hippocampus, which is considered the control center of memory. Larger brain volumes provide better protection against neurodegeneration than smaller ones." However, the dimensions of the brain regions do not increase linearly with physical activity. The research team found the largest, almost sudden volume increase when comparing inactive and only moderately physically active study participants - this was particularly evident in older individuals over the age of 70.

"In principle, this is very good news - especially for those who are reluctant to exercise. Our study results indicate that even small behavioral changes, such as walking 15 minutes a day or taking the stairs instead of the elevator, may have a substantial positive effect on the brain and potentially counteract age-related loss of brain matter and the development of neurodegenerative diseases. In particular, older adults can already profit from modest increases of low intensity physical activity." Young and somewhat athletic subjects who usually engaged in moderate to intense physical activity also had relatively high brain volumes. However, in even more active subjects, these brain regions were slightly larger. Also here it showed: the more active, the greater the effect, although at high levels of physical activity, the beneficial effects tended to level off.

To characterize the brain regions that benefited most from physical activity, the research team searched databases for genes that are particularly active in these brain areas. "Mainly, these were genes that are essential for the functioning of mitochondria, the power plants of our cells." This means that there are particularly large numbers of mitochondria in these brain regions. Mitochondria provide our body with energy, for which they need a lot of oxygen. "Compared to other brain regions, this requires increased blood flow. This is ensured particularly well during physical activity, which could explain why these brain regions benefit from exercise."

The immune system is a versatile and dynamic body organ which offers survival and endurance of human beings in their hostile living environment. However, similar to other cells, immune cells are hijacked by senescence. The ageing immune cells lose their beneficial functions but continue to produce inflammatory mediators which draw other immune and non-immune cells to the senescence loop. Immunosenescence has been shown to be associated with different pathological conditions and diseases, among which atherosclerosis has recently come to light. There are common drivers of both immunosenescence and atherosclerosis; e.g. inflammation, reactive oxygen species (ROS), chronic viral infections, genomic damage, oxidized-LDL, hypertension, cigarette smoke, hyperglycaemia, and mitochondrial failure. Chronic viral infections induce inflammaging, sustained cytokine signaling, reactive oxygen species generation and DNA damage which are associated with atherogenesis.

Recent data indicate that chronic viral infections manipulate the pathways involved in replicative senescence (RS), oncogene-induced senescence (OIS), and possibly genotoxicity-induced senescence (GIS) in immune and non-immune cells. The senescence pathways induced by infectious agents are shared with other senescence inducing stimuli. The induction of senescence in immune cells is more robust in chronic viral infections due to direct stimulation of the immune system by viral antigens. From early childhood, the immune cells of human-beings are challenged with viral infections and fortunately enough, in most cases the virus is contained and even eradicated by immune system. However, continuous encounter with viruses and especially establishment of chronic viral infections in the body results in a state of more inflammatory and less protective immune response.

In atherosclerosis, as one of the old inflammatory conditions and the mother of cardiovascular disease and stroke, immunosenescence is induced both in immune and non-immune cells. Therefore, chronic viral infections, through induction of immunosenescence, may directly or indirectly play a role in development or progression of atherosclerosis. The premature ageing as a result of viral co-infections may also accelerate immunosenescence and inflammatory diseases.

For a long time, immunosenescence has been considered harmful. However, it is noteworthy that immunosenescence is a remodeling and retuning process with increase in some new functions rather than complete decline of immune function. Serum levels of IgG and IgA are increased with age, which is conducive to protecting against viral and bacterial infections effectively in older people. Although the generation of naive T cells and naive B cells continues to decline, the adaptive immune system adjusts to age-related changes and protects the body from most pathogens. Only later in life does the immune function decline gradually, which increases morbidity and mortality in the elderly.

But not all older people suffer from age-related diseases, centenarians can delay the aging process and live up to the limits of human life. Centenarians have a large quantity of anti-inflammatory molecules, such as TGF-β1, IL-10 and IL-1 receptor antagonist (IL-1RA), to counterbalance increased inflammatory molecules, such as IL-1β, IL-6, TNF-α, IL-8, C-reactive protein (CRP) and CXCL9, achieving a dynamic balance between pro-inflammatory and anti-inflammatory levels. In addition, telomere length and telomerase activity are higher in centenarians.

There are currently several strategies to deal with senescence and senescent cells. First of all, rejuvenation of old hematopoietic stem cells (HSCs) may be an effective therapeutic strategy to restore the balance between myeloid and lymphatic systems and the numbers of T and B cells. The involution of the thymus is one of the main features of aging, which might lead to the decrease of T cells, so restoring the structure and function of the aging thymus could reverse immunosenescence. Thymo-stimulatory property of IL-10, leptin, keratinocyte growth factor (KGF) and thymic stromal lymphopoietin (TSLP) may contribute to immune reconstitution of the elderly. IL-7 is a crucial cytokine for T cell development, so IL-7 treatment promotes the expansion of peripheral T cells and the diversity of T cell receptors. Telomerase is a significant component for T cell development, so upregulation of telomerase expression enhances T cell immune response and prolongs lifespan.

Allostatic load is a cumulative measure of the physiological stressors to the body throughout the life course, reflected by damage to multiple biological systems over time. An advantage using allostatic load in predicting health outcomes, as opposed to the use of single biomarkers, is that it captures the effects of stressors on several biological systems simultaneously. Several conditions implicated with high allostatic load have associations with hearing impairment, including diabetes, obesity, sub-clinical atherosclerosis, and vascular degeneration, as have behaviours including poor diet and smoking. However, little work has been carried out into the association between inflammatory biomarkers and hearing impairment, and none (to our knowledge) on the association with allostatic load.

Data were taken from the English Longitudinal Study of Ageing (ELSA), a nationally representative study of people aged 50+ living in England over 3 time points between 2008 and 2014. Allostatic load score was comprised of thirteen different measures available at baseline and 4 years post-baseline (high-density lipoprotein/total cholesterol, triglyceride, fibrinogen, haemoglobin A1c, C-reactive protein, insulin-like growth factor 1 (IGF-1), systolic and diastolic blood pressure, mean arterial pressure, resting pulse rate, peak expiratory flow, BMI and waist circumference), measured using clinical cut-off points for normal biomarker parameters. Hearing acuity was measured with a simple handheld tone-producing device at follow-up 7 years post-baseline, while self-reported hearing impairment was measured at time point.

We included samples of 4,373 and 4,430 individuals for the cross-sectional and longitudinal analysis, respectively. In the cross-sectional model high allostatic load was associated both self-reported (odds ratio, OR = 1.08) and objective hearing loss (OR = 1.10) adjusting for age and sex. In longitudinal modelling, high allostatic load was associated with both audiometric (OR = 1.11) and self-reported hearing impairment (OR = 1.08) adjusting for age and sex. Thus prolonged high allostatic load was associated with risk of hearing impairment.

Researchers compared young mice with induced hypertension to older mice without hypertension to assess the potential relationship of hypertension to bone aging. A group of 12 young mice (4 months old) were given angiotensin II for six weeks, a hormone that leads to high blood pressure. A group of 11 older mice (16 months old) also received of angiotensin II for six weeks. Two control groups of 13 young mice and 9 old mice received a buffer solution that did not include angiotensin II, and these mice did not develop high blood pressure.

After six weeks, researchers analyzed the bones of mice from all four groups using micro-computed tomography. When compared to the young mice without hypertension, the young mice with induced hypertension had a significant 24% reduction in bone volume fraction, an 18% reduction in the thickness of the sponge-like trabecular bone located at the end of long bones, such as femurs and the spinal column, and a 34% reduction in estimated failure force, which is the ability of bones to withstand different types of force.

In contrast, the older mice who were given the angiotensin-II infusion did not exhibit similar bone loss. During the study, however, the old mice, with or without high blood pressure, exhibited a reduced bone quality similar to that of the hypertensive young mice. To assess the impact of inflammation on bone health of the mice, researchers analyzed the bone marrow using flow cytometry. This tool allowed researchers to identify individual cells and to sort out specific immune cells. In the hypertensive young mice, they found an increase in the number of inflammatory signaling molecules, indicating an increase in inflammation in the bones when compared to the young mice that did not receive angiotensin II.

"This increase in active immune cells tells us that the older mice are more inflamed overall, and that a continued state of inflammation, whether they had high blood pressure or not, may have an impact on bone health. It appeared that high blood pressure was adjusting the bone remodeling process toward bone loss, rather than bone gain or bone equilibrium, in the hypertensive young mice. As a result, bones will be weaker, leading to an increased risk for osteoporosis and fragility fracture. In humans, this might mean that we should screen for osteoporosis in people with high blood pressure."

The lung is exposed to a myriad of substances with every breath we take. To protect itself from pollutants, dust, particulate matter, allergens, viruses, bacteria, and fungi that exist in the air around us, the lung has evolved a highly tuned innate immune system. One of the first lines of defense against inhaled matter is mucociliary clearance, which is performed by the airway epithelium of the trachea and the central conducting airways.

The conducting airways of the lung are lined by ciliated airway epithelial cells. The ciliated cells are covered by a thin periciliary sol layer that is approximately the same height as the cilia. The periciliary layer is low viscosity and facilitates ciliary beating. Interspersed with the ciliated cells are mucus-producing cells. In the conducting airways, goblet cells are the most prevalent mucus-producing cell. The apical cytoplasm of goblet cells is filled with membrane-bound secretory granules filled with mucins. These granules are secreted to form the mucus layer. Mucus is a thick, gel-like material that consists of water, salts, mucins, proteoglycans, lipids, and proteins. This blanket of mucus is free-floating over the respiratory epithelium. When an insoluble foreign substance is inhaled and deposits in the airway, it is trapped in a blanket of mucus. The cilia then beat in a coordinated manner to expel mucus from the lungs.

Cough is also an important mechanism of clearing the airways. In humans, cough increases as mucociliary clearance slows. Impairment in cough sensitivity can lead to recurrent pneumonia. Mucociliary clearance can be affected by changes in the quantity, viscosity, or composition of mucus or changes in ciliary number, structure, beating, or coordination. Aging can cause changes in many of the mucociliary clearance apparatus components, include structural changes in the airway epithelium, changes in cilia function, as well as changes in mucus quality, leading to a higher propensity for chronic lung disease and infection with aging.

A newly developed agonistic antibody reduced the amyloid pathology in mice with Alzheimer's disease, signaling its promise as a potential treatment for the disease. Researchers found that a tetra-variable domain antibody targeting the triggering receptor expressed on myeloid 2 (TREM2) - dubbed TREM2 TVD-lg - reduced amyloid burden, eased neuron damage, and alleviated cognitive decline in mice with Alzheimer's disease.

TREM2 is a single-pass receptor expressed by microglia - supportive cells that function as scavengers in the central nervous system. The antibody increased TREM2 activation and promoted phagocytosis of amyloid and microglia survival. Microglia play a crucial role in the removal of amyloids that cluster around amyloid-beta plaques, a hallmark of Alzheimer's disease. While previous research has shown that TREM2 plays an important role in the pathophysiology of Alzheimer's disease, the recent findings suggest that increasing TREM2 activation could have therapeutic effects such as improved cognition.

Researchers looked at a health care database in Spain and identified people who were at least 40 years old and had a first stroke over a 14-year period. Each person who had a stroke was compared to five people of the same age and sex. There were 14,322 people who had a stroke and 71,610 people who did not have a stroke. Then the researchers looked at whether people had received the influenza vaccine at least 14 days before the stroke or before that same date for those who did not have a stroke.

A total of 41.4% of those who had a stroke had received the flu shot, compared to 40.5% of those who did not have a stroke. But the people who got the shot were more likely to be older and to have other conditions such as high blood pressure and high cholesterol that would make them more likely to have a stroke. Once researchers adjusted for those factors, they found that those who received a flu shot were 12% less likely to have a stroke than those who did not.

The researchers also looked at whether the pneumonia vaccine had any effect on the risk of stroke and found no protective effect. Since the study was observational, it does not prove that getting the flu shot reduces the risk of stroke. It only shows an association. There could be other factors that were not measured that could affect the risk of stroke.

Accelerated aging makes adults more vulnerable to chronic diseases and death. Whether childhood adversity is associated with accelerated aging processes, and to what extent lifestyle mediates the association, remain unknown. Out objective was to examine the associations of childhood adversity with a phenotypic aging measure and the role of unhealthy lifestyle in mediating these associations. A retrospective cohort analysis was conducted using data from adult participants in the UK Biobank baseline survey (2006-2010) and online mental health survey (2016). Childhood adversity, including physical neglect, emotional neglect, sexual abuse, physical abuse, and emotional abuse, was assessed retrospectively through the online mental health survey (2016).

A phenotypic aging measure, phenotypic age acceleration, was calculated, with higher values indicating accelerated aging. Body mass index, smoking status, alcohol consumption, physical activity, and diet were combined to construct an unhealthy lifestyle score (range, 0-5, with higher scores denoting a more unhealthy lifestyle). A total of 127,495 participants aged 40 to 69 years were included. Each individual type of childhood adversity and cumulative childhood adversity score were associated with phenotypic age acceleration. For instance, compared with participants who did not experience childhood adversity, those who experienced 4 (β = 0.296) or 5 (β = 0.833) childhood adversities had higher phenotypic age acceleration in fully adjusted models. The formal mediation analysis revealed that unhealthy lifestyle partially mediated the associations of childhood adversity with phenotypic age acceleration by 11.8% to 42.1%.

In this retrospective cohort study, childhood adversity was significantly associated with acceleration of aging and, more importantly, unhealthy lifestyle partially mediated these associations. These findings reveal a pathway from childhood adversity to health in middle and early older adulthood through lifestyle and underscore the potential of more psychological strategies beyond lifestyle interventions to promote healthy aging.