Cryopreservation has multiple and important applications, particularly in medicine. The fact that it can significantly slow down all biochemical reaction kinetics renders cryopreservation highly attractive as a means to preserve organs and therefore facilitate the transplantation process. The lack of organ availability constitutes a major challenge and a significant medical burden for society. According to the World Health Organization (WHO), only 10% of the worldwide need for organ transplantation was met in 2010. The lack of transplantable organs stems partially from a shortage of suitable donated organs, but more importantly from the lack of preservation capability. Although the number of transplanted organs is much lower than what is actually needed worldwide, it was estimated that approximately two thirds of potential donor hearts are discarded.

Kidneys and hearts have been the most widely studied organs, but neither has been consistently recovered after cooling to temperatures lower than -45 °C. Nevertheless, sporadic survival of kidneys has been claimed after cooling to lower temperatures. Along those lines, researchers reported success in vitrifying a rabbit kidney at -130 °C which was rewarmed using a special conductive warming technique combined with perfusion. After warming, the kidney was transplanted into a recipient rabbit that lived for 48 days with a working kidney before being sacrificed.

Cryopreservation is an interdisciplinary endeavour between medicine, biology, bioinformatics, chemistry and physics. The main challenges still to overcome are scaling up current methods to larger volumes and complex tissues. The larger the organ, or tissue volumes to be vitrified, correspondingly more time is required to cool and warm the organ. Not only thermal conductivity is an issue here but cryoprotective agent (CPA) viscosity limits for perfusion systems play a role. The protocols for cell lines, or even small tissues, such as sperm, eggs, or corneas, cannot be replicated in larger human organs, which necessitate toxically high CPA concentration to inhibit ice formation during the longer time spent between the melting temperature and the glass transition temperature, and of course gives more time for toxic insults to accumulate.

The best techniques to get around these problems in small tissues use combinations of CPAs to reduce toxic effects of any single agent, using CPAs with weak water interactions to minimise disruption of hydration layers around biomolecules, using CPAs with mutual toxicity neutralisation effects, and reducing penetrating CPA concentrations by adding non-penetrating CPAs and ice blockers. Nonetheless, little is known about the mechanisms at work.

The challenges in cryobiology are not insurmountable. Future research will focus on ever more complex ways to prevent ice formation and mitigate cryoprotectant toxicity; novel cryoprotectants which exert disproportionately large cryoprotective effects compared to their concentration, in silico molecular modelling, and enhanced understanding of the processes that occur during cryopreservation will all be employed. One could envision a universal cryoprotectant solution, suitable for use in a range of tissue types, and physical advancements enabling high cooling and warming rates, or the manipulation of ice formation for large volume vitrification or freezing.

Whilst the concepts have been long known, the dedicated field of cryobiology dates back only around 70 years. In that time, it has advanced from freezing spermatozoa using glycerol, to vitrifying tissues, and even small organs using complex multi-component solutions. This is remarkable progress given that cryopreservation is as yet a relatively niche field of study, without garnering much attention in schools or undergraduate courses and utilising a fraction of the funding which is allocated to other causes. As such, there are still many opportunities that lie ahead, from short-term improvements in transplantation biology, to ambitions that may once have been viewed as science fiction, such as the building of organ banks or long-term suspended animation.

The aging process is associated with pervasive physiological declines that are exemplified by reductions in size and function of skeletal muscle (i.e., sarcopenia). Given the association between sarcopenia with adverse health outcomes (e.g., falls, fractures, and mobility limitations) and mortality, a more definitive understanding of the biological mechanisms underlying sarcopenia is warranted.

The regulation of skeletal muscle mass is dictated by temporal fluctuations in muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Though the effect of aging on whole body protein turnover was initially a subject of great contention, it is now generally accepted that healthy aging is not accompanied by accelerated MPB. Furthermore, comparable rates of basal MPS and turnover have been observed in healthy older and younger adults. However, in older animals and humans alike, the sensitivity of MPS to anabolic stimuli, such as protein feeding, is substantially diminished when compared with that in the young. This blunted anabolic responsiveness, termed anabolic resistance, is highly characteristic of aging skeletal muscle, and much effort is being devoted to delineating the etiology of this phenomenon. Greater insight into this area may help to optimize the rehabilitative role of protein intake for the maintenance and/or recovery of skeletal muscle tissue in older adults.

The gut microbiota refers to the collective of bacteria, archaea, viruses, and eukaryotic microbes that reside in the gastrointestinal tract. Though best known for its role in nutrient uptake, the gut microbiome is also intricately connected to a diverse array of physiological systems; influencing metabolic function, protecting against pathogens, and modulating immune response. Recent studies by several independent research groups have provided evidence for a bidirectional gut-muscle axis with profound implications for aging skeletal muscle and sarcopenia. As studies supporting a role for the gut microbiome in regulating muscle mass and function continue to accumulate, whether baseline microbial signatures may influence anabolic potential is deserving of deeper inquiry.

The purpose of this review will be to provide evidence in support of the hypothesis that age-associated changes in gut microbiota composition contribute to anabolic resistance following protein feeding in older adults that underlie sarcopenia. We will begin by outlining how changes in gut microbiota that are hallmarks of aging may impact protein digestion and amino acid absorption, reduce circulating amino acid availability, contribute to anabolic hormone deficiencies or impair responsiveness, and play a role in intramuscular signaling deficits - all of which may underlie age-related anabolic resistance.

A bidirectional gut-muscle axis with implications for aging skeletal muscle size, quality, and function has been proposed. Extending on this aging gut-muscle axis, we propose that age-related changes in gut microbiota may detract from the anabolic response of skeletal muscle to protein feeding in older adults. Intriguingly, many of these adverse microbial modifications seem to be avoided in long-lived models of highly successful aging. Through the above, we describe how commonly observed age-related changes in the gut microbiome may compromise anabolic responsiveness through their impact on protein digestion and amino acid absorption, circulating amino acid availability, anabolic hormone production and responsiveness, and anabolic intramuscular signaling.

While some of these age-associated gut microbiome alterations may simply be a product of the natural aging process, we believe that lifestyle modification (i.e., improved diet, exercise, sleep, and reducing medication use) may help to preserve gut microbial equilibrium in a manner that would be anticipated to maintain anabolic capacity in older years. To validate this hypothesis, interventional studies attempting to manipulate microbial ecology as a means to potentiate muscle protein synthetic responses to anabolic stimuli (i.e., protein feeding) in older individuals are needed.

Here we show that NAD+ supplementation by the NAD+ precursor nicotinamide riboside (NR) can restore a youthful number of osteoprogenitor cells and attenuate skeletal aging in female mice. These, along with the findings that the levels of NAD+ decline with age in osteoblast progenitors, strongly suggest that NAD+ is a major target of aging in osteoblastic cells. A decrease in NAD+ was also seen in bone marrow stromal cells from 15-month-old when compared to 1-month-old mice. In agreement with our findings, long-term administration of NMN increased bone mineral density in male C57BL/6 mice. In contrast, administration of NMN to 12-month-old mice for only 3 months was not sufficient to alter bone mass.

We also found that the protein levels of Nampt in osteoblastic cells from old mice were lower than in cells from young mice. These along with the findings that deletion of Nampt in mesenchymal lineage cells is sufficient to decrease bone mass support the premise that the age-associated decrease in NAD+ in osteoblast progenitors attenuates bone formation. Further support is provided by evidence that NR administration increases osteoprogenitor number and mineralizing surface in aging mice. In tissues such as muscle and intestine, progenitor cells are critical targets of the anti-aging effects of NR. Nonetheless, the systemic nature of NR treatment precludes definitive conclusion about the target cells responsible for the beneficial effects on the skeleton.

We and others have shown that osteoprogenitors from old humans or mice exhibit markers of cellular senescence. Elimination of senescent cells via genetic or pharmacologic manipulations increases bone mass in aged mice, suggesting that cellular senescence contributes to skeletal aging46. Our present findings that NR administration decreases markers of senescence in osteoblast progenitors from old mice provide strong support for the contention that a decline in NAD+ is a major contributor to the age-associated bone cell senescence. This contention is further supported by evidence that a decrease in NAD+ exacerbates replicative senescence in bone marrow-derived stromal cell cultures. NR administration also attenuates cellular senescence in brain and skin of aged mice. Interestingly, in macrophages and endothelial cells Cd38 expression can be induced by factors associated with the senescence-associated secretory phenotype (SASP), suggesting that cellular senescence re-enforces the decline in NAD+.

Based on the results of the present work, we propose that intrinsic defects in osteoblast progenitors that cause a decrease in NAD+ contribute to the age-related decline in bone formation and bone mass. Repletion of NAD+ with precursors such as NR, therefore, may represent a therapeutic approach to age-associated osteoporosis as it does for other age-related pathologies.

The skin is the largest organ in the body, and carries out multiple vital functions, including protective barrier functions against the loss of moisture and mechanical, UV, and other injuries, immune defense functions, as well as sensory functions. For maintaining its integrity and multifaceted performances, skin relies on a range of different cell types that compose and support its layered organization, each expressing specific molecules that together facilitate physical cell interactions and communication between them, as well as specialized functions.

The gradual decline in the production of many of those molecules is associated with the natural aging process of skin. Separately, a plethora of skin diseases are driven by mutations in single genes that can strike much earlier in life. In both cases, targeted therapeutics that could slow skin aging and directly interfere with the disease pathology of monogenic skin diseases are not available. Commonly applied treatments are merely palliative, reducing the severity symptoms or simply masking the visible damage caused to the skin without actually addressing the condition.

To overcome the lack of truly curative and targeted treatments, a multidisciplinary team has developed a comprehensive gene therapy platform that combines a new computational target discovery platform with improved skin cell-specific adenovirus-associated virus (AAV) gene delivery vehicles, and a novel biomaterials-mediated local delivery of the genetic payloads to affected areas of the skin. Strategically targeting both disease (short-term) and aging (long-term), this next generation skin gene therapy platform builds on the insight that the pathology of genetic diseases often recapitulates specific age-related degenerations.

Fortuitously, researchers found that key targets in aging biology could be leveraged as therapeutics for monogenic diseases, as the genes affected in such diseases were also powerful determinants of the aging process. Using their new-found understanding of aging dynamics, the team has built a time-resolved genetic network of skin aging, and is currently validating novel age-driving genetic targets identified from the resulting map in cell and animal studies.

I'm working on an Institute Project called MRBL, which essentially enables in situ genetic engineering of the skin. It's a platform technology and has a variety of applications. We started the project looking at the hardest problem - how to solve skin aging at the molecular level. Our gene-potentiating technology could make skin cells go back to their younger state, causing a true rejuvenating effect, and we're trying to get there by modifying the levels of the right fingerprint of genes in the skin.

This technology can also be applied to monogenetic skin diseases, which are diseases that are controlled by the malfunction of a single gene. These conditions manifest in phenotypes like blistering skin and numerous open wounds. With MRBL we are creating novel therapeutics that can correct the levels of such dysfunctional genes or even permanently correct mutations causing injured skin using a skin cell-specific, minimally invasive, adenovirus-associated (AAV)-based gene delivery system.

Beyond that, we are using the same technology to try and leverage the skin as a bioreactor for the production of neutralizing antibodies directly in the body that could help fight HIV, COVID-19 or other infectious diseases. In these instances, the skin is not being treated because it is sick or aging, but instead used as a "factory" to produce therapeutic antibodies or even foreign proteins that stimulate the immune system in a protective way.

Lifespan is one of the most variable life history traits in the animal kingdom, lasting from days to centuries. Despite intensive investigation, there are still many grey areas in our understanding of the factors which contribute to the variability of lifespan. Humans are among the fortunate animals which have an unusually long lifespan compared to their similar sized mammals. On the flip side, the long lifespan of humans and large genetic heterogeneity are important reasons why it is very difficult to use humans as models to study ageing or longevity or test the efficacy of anti-ageing interventions. Ageing studies on humans often require a very large cohort of people and can potentially be affected by many confounding factors. As a consequence, most studies involving ageing, lifespan, and anti-ageing interventions are based on model systems.

In the evolutionary history after divergence from the great apes, the most recent of our primate ancestors, humans have completed almost 300,000 generations. During this period, the lifespan of H. sapiens has almost doubled. The increased longevity of humans is, in part, attributable to environmental changes; improved food, water, and hygiene; reduced impact of infectious disease; and improved medical care at all ages. However, the above factors had an opportunity to play some role in increasing lifespan only in the last 2 centuries. The dramatic increase in human lifespan compared to our nearest ancestors, should, therefore, must have other valid explanations. It is highly conceivable that forces of natural selection may have played vital role in increasing the basic longevity of humans.

Zugzwang is a German word with the literal meaning "compulsion to move." This word is frequently used in chess to describe a situation when a player gets a disadvantage because it is his turn to play, but all the available moves are bad. In Zugzwang position, any move the player makes will clearly weaken his position. Here, I propose that at this stage of evolution, humans may face the Zugzwang problem. Scientific research and the understanding of the hallmarks of ageing now provide humans with more than a dream to extend lifespan. However, it must be taken into consideration that natural selection has already played its part in extending human lifespan much beyond the expectation. All possible mechanisms which can increase longevity in lower animals have already been exploited by natural selection to stretch human lifespan. Any artificial attempt to tinker, through any possible intervention, with the signalling pathways or transcription factors to achieve a longer lifespan may actually be disadvantageous to humans.

Humans may thus be considered to be in the Zugzwang state. Humans may have already achieved or approached the maximum life­span, and further lifespan extension may be very difficult or impossible. Documented record of human longevity for the last 100 years (with a conservative estimate of data from 8 billion individuals) shows that the limit of human lifespan is around 122 years; the fact that no individual has lived beyond this limit is a clue to the validity of the Zugzwang hypothesis.

Several dietary and pharmacological treatments are known to extend lifespan, including rapamycin (Rapa), acarbose (ACA), and 17-α-estradiol (17aE2). The mechanisms by which these treatments lead to lifespan extension are not well understood. Rapa inhibits the activity of the mammalian target of rapamycin (mTOR), leading at optimal doses to 20%-25% lifespan extension in male and female mice. ACA is an inhibitor of the α-glucosidase hydrolase enzymes and α-amylases, enzymes that digest carbohydrates in the small intestine, leading to reduction in glucose absorption and in peak glucose levels in blood. ACA extends lifespan by around 20% in males and around 5% in female mice. 17aE2 is a non-feminizing steroid that has a reduced affinity for the classical estrogen receptors. 17aE2 has reproducible and robust effects on male median and maximum lifespan, with no lifespan effect in females.

We hypothesized that Rapa, ACA, which both increase mouse lifespan, and 17α-estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long-lived Snell dwarf, PAPPA knockout, and growth hormone receptor knockout mice. The long-lived mutant mice exhibit reduction in mTORC1 activity, declines in cap-dependent mRNA translation, and increases in cap-independent translation (CIT).

Here, we report that Rapa and ACA prevent age-related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age-related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6-methyl-adenosine to mRNA and thus a trigger for CIT, also showed an age-dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT-dependent proteins may represent a shared pathway for both long-lived-mutant mice and drug-induced lifespan extension in mice.

The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage.

Herein, we sought to clarify the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions.

In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages, and dendritic cells in the heart.

Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.

Aging manifests in a continuous decline of organismal homeostasis. Accumulating defects on the cellular level can result in cellular dysfunction that impairs normal physiology. This damage can be of extrinsic origin e.g., mutagenic radiation and toxins, or intracellular origin, like harmful reactive oxygen species (ROS) generated by defective mitochondrial respiration, advanced glycation end products or the accumulation of toxic protein aggregates. The consequences of such harm are particularly devastating to post-mitotic, fully differentiated cells with low cellular turnover rates, such as neuronal cells and cardiomyocytes.

To mitigate the detrimental effects of extrinsic and intrinsic harms, eukaryotic cells have developed various protective mechanisms. One such mechanism is proteostasis, a collective term for a network of protein quality control and degradation pathways that ensure the normal expression, folding, and turnover of proteins. During aging, proteostasis, like other cellular functions, suffer from a progressive decline, which renders the body more vulnerable to damage and age-related diseases.

In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.

Why neurogenesis is attenuated in elderly individuals is an intriguing question that has raised renewed interest. Mechanisms associated with declined neurogenesis in the aged brain have been attributed to inflammatory cytokines. More recently, a specific role for interferon-γ (IFN-γ) produced by CD8-expressing cytotoxic T cells has been implicated. These observations suggest a scenario in which neurogenesis, at least in part, is regulated by immune cells within the aging brain. This raises several interesting questions with regards to the characteristics of specific immune cells within the brain, the signals for their expansion and maintenance, and their role in affecting neurogenesis and cognition during normal brain aging.

Further detailed insights into these processes have now been provided. In a recently published study, researchers analyzed the subtypes, frequencies, and location of immune cells in young and aged brains. Strikingly, an abundant population of natural killer (NK) cells in the dentate gyrus of brains from old humans was observed. NK cells are innate lymphocytes, with some adaptive features, that normally play a critical role in fighting virus infections and tumors. These NK cells outnumbered neutrophils, monocytes, and adaptive T lymphocytes and B lymphocytes in the brain, and were characterized by the expression of specific activation and cytotoxicity markers. These and other observations led the authors to conclude that NK cells may accumulate in specific regions of the human brain with age, in particular in the dentate gyrus. Similar observations were made in mouse studies.

It was found that the NK cell chemokine CCL3 and the growth factors GM-CSF, IL-2 and, particularly, IL-27 were produced in relatively high amounts in the interstitial fluid of the aged dentate gyrus. In studies determining whether IL-27 derived from aged neuroblasts was necessary for local expansion and accumulation of NK cells in the aged dentate gyrus, it was observed that an IL-27-neutralizing antibody blocked these effects. Together, these and other results suggested that neuroblasts sustain NK cells and augment their cytotoxicity in the aged dentate gyrus mediated, at least in part, via IL-27.

In summary, in the brain, NK cells increase with age. They predominantly reside in the dentate gyrus, a neurogenic niche where neuroblasts are also found. As the brain ages, neuroblasts undergo cellular senescence, start to express RAE-1, and produce high levels of IL-27 that induces expansion of NK cells. Notably, RAE-1 is a ligand for the NK cell activation receptor NKG2D. These age-related alterations trigger cytotoxic activity by the NK cells leading to loss of neuroblasts, concomitantly preventing regeneration of neurons resulting in cognitive decline.

Mitochondria, which can be briefly described as the energy provider of cells, have been shown in recent studies to be interdependent with gut bacteria. In fact, many diseases associated with mitochondrial dysfunction in humans, such as Parkinson's and Crohn's have been linked to changes in the gut microbiome in many previous studies.

"Studying horses is a good way to assess the link between gut bacteria and mitochondria, because the level of exercise, and thereby mitochondrial function, performed by a horse during an endurance race is similar to that of a human marathon runner. For this study we took blood samples from 20 healthy horses of similar age and performance level, at the start and end of the International Endurance Competition of Fontainebleau, an 8-hour horse race in France. These samples provided information about the chemical signals and expression of specific genes, which is the process by which DNA is converted into instructions for making proteins or other molecules. To understand the composition of the horse's gut bacteria metabolites, we obtained fecal samples at the start of the race."

The researchers found that certain bacteria in the gut were linked to the expression of genes by the mitochondria in the cells. Furthermore, the genes that were expressed, or "turned on", were linked to activities in the cell that helped it to adapt to energetic metabolism.

"Interestingly, mitochondria have a bacterial origin - it is thought they formed a symbiotic relationship with other components to form the first cell. This may explain why mitochondria have this line of communication with gut bacteria. Improving our understanding of the intercommunication between the horse and the gut microbiome could help enhance their individual performance, as well as the method by which they are trained and dietary composition intake. Manipulating the gut microbiota with probiotic supplements as well as prebiotics, to feed the good bacteria, could be a way for increasing the health and balance of the microbiome and horses, to better sustain endurance exercise."

How does an idea that is too unconventional for mainstream channels get funded? Today, the concept of longevity research is rapidly gaining adoption, but it wasn't long ago that angel investors and the rare NIH grant were the only options for people fighting for increased longevity. Longevity enthusiasts are likely to know names like Peter Thiel, Dmitry Itskov, J. Craig Venter, Sergey Brin, Larry Ellison, and Jeff Bezos for their personal contributions, both as philanthropists and investors. Among angel investors, Jim Mellon was one of the earliest adopters of longevity research. While his fortune has come from various other sectors, he founded Mann Bioinvest, published Cracking the Code, and started praising the healthy longevity strategy back in 2012. With all the progress and setbacks of the last decade, Jim remains optimistic about the field, recently claiming that the world is on the brink of three major revolutions, with increased longevity being one of them.

In biotech, Jim Mellon is most well-known for his role in Juvenescence, which is both a book he authored on biotech investment and a longevity company he co-founded. Juvenescence has its hand in tissue regeneration and cell therapy approaches to healthy longevity via AgeX Therapeutics and LyGenesis. While still at the preclinical stage, LyGenesis has been perhaps the most successful tissue engineering and regenerative medicine company thus far. Separately from Juvenescence, Jim Mellon also played a role as chairman of Regent Pacific during its acquisition of AI firm Deep Longevity last year. He's also invested in Repair Biotechnologies and various other companies outside the scope of Juvenescence.

Beyond his investments, Jim Mellon has also made various donations to longevity nonprofits in recent years, including the UCL Institute of Healthy Ageing, Methuselah Foundation, and SENS Research Foundation, among others. In 2020, he donated £1 million to Oriel College in order to support and advance the study of Longevity Science at Oxford University, the largest donation of its kind.

For better or worse, high-net-worth individuals are imperative to the translation of treatments from the bench to bedside. While some media organizations make negative comments that billionaires are simply attempting to buy their own immortality without regard for anyone else's health, these concerns are largely overblown. Overall, few people have done as much to increase human longevity as Jim Mellon. Beyond putting up his own capital, he's also played a major role in convincing others to do the same, thereby accelerating longevity research and moving us towards a healthier future.

Here we report that COVID-19 hospitalisation rates follow an exponential relationship with age, increasing by 4.5% per year of life. This mirrors the exponential decline of thymus volume and T-cell production (decreasing by 4.5% per year). COVID-19 can therefore be added to the list of other diseases with this property, including those caused by MRSA, West Nile virus, Streptococcus Pneumonia, and certain cancers, such as chronic myeloid leukemia and brain cancers. In addition, incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. For under 20s, COVID-19 incidence is remarkably low.

A Bayesian analysis of daily hospitalisations, accounting for contact-based and environmental transmission, indicates that non-adults are the only age group to deviate significantly from the exponential relationship. Our model fitting suggests under 20s have 53-77% additional immune protection beyond that predicted by strong thymus function alone. We found no evidence for differences between age groups in susceptibility to overall infection, or, relative infectiousness to others. The simple inverse relationship between risk and thymus size we report here suggests that therapies based on T-cell mechanisms may be a promising target.

With an initial focus on developing cosmeceuticals, US start-up Yuva Biosciences aims to harness mitochondrial science to address skin aging and age-related hair loss. The company has developed a natural topical treatment, imminently about to enter human trials, which it hopes will demonstrate an ability to promote hair growth and reduce skin wrinkles.

During founder Keshav Singh's work to explore whether mice induced with mitochondrial dysfunction were more likely to develop cancer, he came across a surprising result. "The first thing we noticed was that, within four weeks or six weeks, these mice developed skin wrinkles, and lost hair. When we restored the mitochondrial function, the hair grew back. So that gave us a direct link between mitochondrial dysfunction and hair loss and skin aging." The results convinced Singh that he should try to discover a compound that would drive similar results and set about testing a range of natural and pharmaceutical products.

"We derived fibroblast cells from these mice, and did a very targeted screening. And, lo and behold, within a month we found a natural compound that can prevent skin wrinkles and hair loss in mice. So we started Yuva Biosciences and have started work towards commercialising both the initial compound discovered, plus a pipeline of compounds, with a focus on natural compounds, because those can go to market as cosmeceuticals. We're actually starting human trials, and we'll be conducting three trials over the next couple months - two for skin, one for hair. And so that'll provide a lot of exciting results and hopefully some exciting products."

A toxic brew of lysosomal lipids, reactive iron atoms, and oxidative stress can spell doom for human neurons. This is the upshot of the first-ever CRISPR screens at the genome-wide level in these cells. Researchers used the genome-editing tool to dial up or down expression of each protein-coding gene in the human neuronal genome. They uncovered a surprising connection between endolysosomal processing and the iron-dependent cell-death pathway called ferroptosis.

Zeroing in on that pathway, the researchers found that in the absence of the lysosomal protein prosaposin (PSAP), glycosphingolipids accumulate in the lysosomes, setting off oxidative stress. This results in a toxic mesh of ferrous ions and peroxidized lipids that can kill neurons via the ferroptosis pathway. The findings connect pathways that have been implicated separately in neurodegenerative disease, and support the idea that iron-rich "aging pigments" of lipofuscin, commonly spotted in older brains, might not be so benign after all.

What is the connection between PSAP and ferroptosis? Examining PSAP knockout neurons, the researchers found that the lysosomes were dramatically enlarged, and chock-full of glycosphingolipids. Strikingly, they found that these lipid-logged organelles were also electron-dense, suggesting they were loaded with iron. In fact, these densities bore an uncanny resemblance to lipid-iron granules called lipofuscin, also known as aging pigment. Lipofuscin soaks up the metal ions from the detritus of iron-rich organelles such as mitochondria, and this iron is thought to provoke the production of reactive oxygen species via the Fenton reaction.

Could this cascade play out in the aging brain? All of the culprits are there. For one, oxidative stress is known to rise in the brain with age, and lysosomal function also flags. Levels of not only lipofuscin, but also reactive iron increase in aging brains and even more so in neurodegenerative disease.

To examine associations between positive airway pressure (PAP) therapy, adherence, and incident diagnoses of Alzheimer's disease (AD), mild cognitive impairment (MCI), and dementia not-otherwise-specified (DNOS) in older adults, this retrospective study utilized Medicare data of 53,321 beneficiaries, aged 65+, with an obstructive sleep apnea (OSA) diagnosis prior to 2011.

Study participants were evaluated using ICD-9 codes for neurocognitive syndromes [AD(n=1,057), DNOS(n=378), and MCI(n=443)] that were newly-identified between 2011-2013. PAP treatment was defined as presence of ≥1 durable medical equipment (HCPCS) code for PAP supplies. PAP adherence was defined as ≥2 HCPCS codes for PAP equipment, separated by ≥1 month. Logistic regression models, adjusted for demographic and health characteristics, were used to estimate associations between PAP treatment or adherence and new AD, DNOS, and MCI diagnoses.

In this sample of Medicare beneficiaries with OSA, the majority (78%) of beneficiaries with OSA were prescribed PAP (treated), and 74% showed evidence of adherent PAP use. In adjusted models, PAP treatment was associated with lower odds of incident diagnoses of AD and DNOS (odds ratio 0.78). Lower odds of MCI, approaching statistical significance, were also observed among PAP users (odds ratio 0.82). PAP adherence was associated with lower odds of incident diagnoses of AD (odds ratio 0.65). In conclusion, airway pressure treatment and adherence are independently associated with lower odds of incident AD diagnoses in older adults. Results suggest that treatment of OSA may reduce risk of subsequent dementia.