Fight Aging! Newsletter, February 28th 2022

Alzheimer's disease (AD), which affects approximately 50,000,000 people worldwide, is the most frequent cause of dementia, constituting a real global health problem. The disease is characterized by the progressive deposition of beta amyloid (Aβ) plaques and tangles of hyperphosphorylated tau neurofibrils, leading to neuroinflammation and progressive cognitive decline. Synaptic dysfunction and neuronal death are at least in part due to the excessive or non-resolving activation of the immune response and any infections or traumatic events affecting the brain (traumatic brain injury) can interfere with central immune homeostasis and accelerate the progression of the disease.

Although several hypotheses have been formulated about the causes of AD pathogenesis and progression, both the onset and the evolution of the disease remain not entirely clear. Therefore, although different therapeutic options have been proposed, many have failed in clinical trials and have not been found to produce significant benefits. It is widely thought that an early diagnosis could be essential to act at the earliest disease stages, but effective and reproducible biomarkers are still far from clinical application.

In recent years, the gut microbiota brain axis (GMBA) has been at the center of biomedical research and it has been suggested as a potential therapeutic target for disorders affecting the central nervous system, including AD. The term "gut microbiota" refers to the commensal microbial community that colonizes the gastrointestinal tract and is constituted by bacteria, fungi, archaea, viruses, and protozoans living in symbiotic relationship with our intestine. Thanks to their active role in regulating host's homeostasis and disease, they are becoming more and more important in the pathogenetic mechanisms of neurodegenerative disorders, such as AD.

Indeed, even though for a long time it was believed that the brain was a totally isolated organ, recent evidence shows that the gut microbiota is at the center of a bidirectional communication between intestine and brain, the so-called microbiota gut-brain axis. This interplay involves the central nervous system (CNS), the autonomic nervous system, the enteric nervous system (ENS), and the hypothalamus-pituitary-adrenal axis (HPA), and it has been reported to be implicated in a number of physiological and pathological processes such as satiety, food intake, glucose metabolism and fat metabolism, insulin sensitivity, and stress. Although the mechanisms underlying this interaction are not fully understood, targeting the microbiota might represent a new diagnostic and therapeutic strategy in AD and in other neurodegenerative diseases.

However, despite several published papers having reviewed possible microbiome-based therapies, to our knowledge a comprehensive view of gut microbiota-based diagnostic and therapeutic approaches is still lacking. Here, based on the main studies addressing gut microbiota dysregulation in AD, we discuss how the microbiota-derived biomarkers might be exploited for early disease detection, and we review the potentiality of probiotics, prebiotics, diet, and fecal microbiota transplantation as complementary therapeutic options for this devastating and progressive disease.

With the acceleration of population aging, the incidence of spinal degenerative diseases has increased significantly, and the main sign is chronic low back pain, which seriously affects patients' quality of life and increases the economic burden on their family and society. Although the aetiologies of spinal degenerative diseases are varied and complex, intervertebral disc degeneration (IDD) is recognized as one of the most important causes. Degenerative disc diseases (DDDs) arising from IDD comprise a series of painful spinal diseases that include discogenic low back pain and lumbar disc herniation. At present, most patients use rest or conservative treatment for pain relief, as well as a variety of drugs such as steroids, local anaesthetics, and other blocking agents. When these methods are ineffective, surgery is often performed to relieve symptoms and improve quality of life. Surgical treatments can also solve pain problems, but have disadvantages such as inability to replace decreased nucleus pulposus (NP) cells, inability to reverse the pathological state of the intervertebral disc (IVD), and potential to cause various intraoperative and postoperative complications.

In recent years, with the rapid development of stem cell technologies that have been effectively applied in haematology, circulation, orthopaedics, and other fields, stem cells have attracted the attention of researchers and clinicians. With in-depth studies on the IVD and IDD as well as its mechanism, many teams have found that combination of stem cell technology and treatment for IDD can not only maintain the normal physiological function and structure of the IVD, but even reverse the IDD cascade. Organic combination of the IVD and stem cell technology has outstanding advantages for IDD treatment and recovery, but remains controversial.

Although cell therapy appears to have great potential for IVD regeneration, there remains a lack of relevant evidence regarding safety, long-term complications, effectiveness in different patient populations, and surgical cost-effectiveness. Further development of stem cell technology and in-depth exploration of IDD in the medical community will determine the future development direction of the organic combination of stem cells and IDD research. First, we need to further explore the interactions between stem cell repair mechanisms and target cells, and strive to identify more targets that promote differentiation. Second, we need to find ways to improve the harsh microenvironment in IDD to provide a better living environment for loaded stem cells. Third, we need to establish methods that can induce and differentiate stem cells from different sources more efficiently and stably, thereby improving the safety of stem cell application. Last, but not the least, it is necessary to optimize the performance of stem cell carrier materials to avoid secondary damage during implantation and further enhance the repair ability of stem cells.

Telomeres are the genomic portions at the ends of linear chromosomes. Telomeric DNA in vertebrates is made of TTAGGG repeats bound by a set of proteins that modulate their biological functions and protect them from being recognized as DNA damage that triggers a DNA damage response (DDR). As standard DNA polymerases cannot fully replicate linear DNA templates in the absence of telomerase, a DNA-template-independent DNA polymerase, and because of nucleolytic processing, DNA replication results in the generation of chromosomes with progressively shortened telomeres. As telomeres reach a critical length, they become unable to bind enough telomere-capping proteins and are sensed as exposed DNA ends, which activates the DDR pathways that, through the induction of the cell cycle inhibitors p21 and p16, arrest proliferation.

Such short telomeres, however, retain a sufficient number of telomere-binding proteins to inhibit DNA repair and avoid fusions, and consequently fuel a persistent DNA damage signal that enforces a permanent DNA damage-induced proliferative arrest. This initiates and maintains cellular senescence, a key contributor to organismal ageing and multiple age-related diseases. Activation of the DDR at telomeres (termed tDDR hereafter) results in the formation of telomere-associated DDR foci (TAFs) or telomere-induced DNA damage foci (TIFs), which are markers of cellular senescence in cultured cells and tissues. Following telomere dysfunction, some cell types may also undergo cell death by apoptosis or autophagy.

In addition to irreversible cell cycle arrest, cellular senescence is characterized by changes in chromatin, gene expression, organelles and cell morphology. Importantly, senescent cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This alters the composition of the extracellular matrix, impairs stem cell functions, promotes cell transdifferentiation and can spread the senescence phenotype to surrounding cells, thereby causing systemic chronic inflammation. SASP is both promoted by DDR and can promote DDR and TAF formation in an autocrine and paracrine fashion.

Although conceptually appealing to explain proliferative exhaustion and cell ageing, telomere shortening is inadequate to explain ageing in non-proliferating, quiescent or terminally differentiated cells. Nevertheless, TAFs and senescence have been reported in ageing post-mitotic cells, including cardiomyocytes, adipocytes, neurons, osteocytes, and osteoblasts. These observations can be explained by an evolutionary perspective by which telomere-binding proteins inhibit DNA repair to maintain the linear structure of chromosomes and to prevent fusions. As a consequence, DNA damage that occurs within telomeric repeats (tDD) resists repair, which causes persistent tDDR signalling and TAF formation also at long telomeres. Endogenous or exogenous DNA damage is constantly generated, and the fraction that occurs at telomeres, which is less efficiently repaired, thus accumulates and induces a senescence-like phenotype.

Therefore, persistent tDDR activation is the shared causative event of both replicative cellular senescence caused by critically short telomeres and the senescence-like state caused by damaged telomeres in non-replicating cells. Although these events may be mechanistically distinct in origin, DNA damage at long telomeres may cause, within the time frame of organismal ageing, degradation or loss of the terminal portions of telomeres, therefore leading to telomere shortening. In the broader context of organismal ageing, the notion that DNA is the only irreplaceable component of the cell makes a strong argument in favour of an apical role of DNA integrity in ageing. The irreparability of telomeres makes it more so.

Alterations to the epigenome are one of the central molecular hallmarks of aging, with potentially vast consequences for the physical and functional characteristics of cells. While a cell's genetic code is essentially fixed, the epigenome is a dynamic master conductor, directing information encoded in DNA to generate the diversity of cells and tissues. In many ways, it is akin to the 'operating system of a cell', controlling cell turnover rate, propagating cellular stress response, and supporting the maintenance and stability of cell populations in tissues. Unfortunately, the epigenetic program is also rewired over the lifespan, leading some to hypothesize that epigenetic change may be the root source of aging-related phenotypes.

One of the most extensively studied epigenetic aging phenomena is the alteration in the pattern of DNA methylation (DNAm). Starting in 2011, DNAm patterns were found to be systematic to a degree that enable their use for developing 'clocks' aimed at estimating aging in cells and tissues. To date, there are more than a dozen such epigenetic clocks being applied to answer questions about aging, disease risk, and determinants of health. Overall, epigenetic clocks have been shown to strongly track with age across a vast array of tissue and cell types - even when trained using only data from blood.

Recently, much of the focus on epigenetic clocks has shifted towards examining them in the context of cellular reprogramming. Intriguingly, the conversion of somatic cells into induced pluripotent stem cells (iPSCs) via expression of Yamanaka factors can reverse the epigenetic aging signal - taking cells all the way back to a predicted age of around zero. However, it remains to be shown to what extent this truly represents an aging rejuvenation event. It is also unclear whether all DNAm age changes that accumulated within a cell are reversed, and if not, what the specific relevance is for those that are, versus are not, "reprogrammed".

This lack of insight stems from an overall deficiency in mechanistic understanding of the changes captured by epigenetic clocks - what initiates these epigenetic changes and how or why are they implicated in disease etiology? Moreover, the debate over whether they are causal drivers versus casual passengers of aging has yet to be settled. The major obstacle we observe in uncovering mechanistic understanding relates to the way epigenetic clocks have been constructed. Epigenetic clocks are composite variables developed from a top-down perspective that combines input from typically hundreds to thousands of CpGs that appear to change with aging, without regard to the underlying biology. As such, they likely are comprised of many different subtypes of methylation patterns-each with its own causal explanations and functional consequences.

In this paper we combined computational and experimental approaches to deconstruct epigenetic clocks and group CpGs into smaller functionally related modules, from which epigenetic aging mechanisms can be more easily discovered. We demonstrate that not all signals captured in the clocks are equal when it comes to morbidity/mortality risk. We also show that reprogramming is concentrated on a few specific modules, yet the discrepancy in response across CpGs is not decipherable at the level of the whole clock.

Overall, two modules stand out in terms of their unique features. The first is one of the most responsive to epigenetic reprogramming; is the strongest predictor of all-cause mortality; and shows increases with in vitro passaging up until senescence burden begins to emerge. The second module is moderately responsive to reprogramming; is very accelerated in tumor versus normal tissues; and tracks with passaging in vitro even as population doublings decelerate. Overall, we show that clock deconstruction can identify unique DNAm alterations and facilitate our mechanistic understanding of epigenetic clocks.

It is well established that kidney function decreases with age. Many studies have shown this decrease in kidney function to be manifested by a decrease in kidney size as well as decreased glomerular filtration rate (GFR). Therefore, a substantial portion of the population may have GFRs in a range indicative of chronic kidney disease. As kidney disease does not become apparent until there is a remarkable loss of kidney function, there are tens of millions of individuals with some degree of chronic kidney disease. Histological studies have shown that the percentage of glomeruli showing signs typical of glomerulosclerosis increases with age. Cellular senescence has a central role in the aging process and has been studied intensively. The major molecular pathways involved in cellular senescence appear to be those regulated by p53, p16INK4A, and downstream cyclin-dependent-kinase inhibitors. Wnt signaling also likely has a role in the aging process.

GSK3 is an enzyme that has two highly conserved isoforms, GSK3α and GSK3β. As indicated by its name, GSK was originally identified as a regulator of glucose metabolism, acting downstream of insulin. GSK3β, the isoform that has received greater study, is probably best known, beyond its role in regulating glycogen synthesis, for its ability to phosphorylate β-catenin, targeting it for proteasomal degradation, thereby suppressing canonical Wnt signaling. Indeed, for many years the most commonly accepted approach to boosting canonical Wnt signaling has involved the use of GSK3β inhibitors. However, the enzymatic activity of GSK3β is able to phosphorylate serines and threonines on a wide range of proteins, such that GSK3β activity may have pleiotropic effects on cell physiology and particularly on cell senescence.

As a multitasking protein kinase recently implicated in a variety of renal diseases, glycogen synthase kinase 3β (GSK3β) is overexpressed and hyperactive with age in glomerular podocytes, correlating with functional and histological signs of kidney aging. Moreover, podocyte-specific ablation of GSK3β substantially attenuated podocyte senescence and glomerular aging in mice. Mechanistically, key mediators of senescence signaling, such as p16INK4A and p53, contain high numbers of GSK3β consensus motifs, physically interact with GSK3β, and act as its putative substrates.

In addition, therapeutic targeting of GSK3β by microdose lithium later in life reduced senescence signaling and delayed kidney aging in mice. Furthermore, in psychiatric patients, lithium carbonate therapy inhibited GSK3β activity and mitigated senescence signaling in urinary exfoliated podocytes and was associated with preservation of kidney function. Thus, GSK3β appears to play a key role in podocyte senescence by modulating senescence signaling and may be an actionable senostatic target to delay kidney aging.

According to the classic theory of life history evolution, ageing evolves because selection on traits necessarily weakens throughout reproductive life. But this inexorable decline of the selection force with adult age was shown to crucially depend on specific assumptions that are not necessarily fulfilled. Whether ageing still evolves upon their relaxation remains an open problem. Here, we propose a fully dynamical model of life history evolution that does not presuppose any specific pattern the force of selection should follow.

In our model, ageing is evolutionarily inevitable in a dynamical sense irrespective of the genetics of fecundity and survival. Selective forces may at times be stronger in late life than in earlier life. But, as we show, this property pertains to either a transient or an unstable state, which is eventually abandoned. An ever-declining force with age is not an intrinsic property of selection and the one driver behind the evolution of ageing, as the classic theory implicitly assumes. Instead, a persistent, age-related weakening of selective forces is itself a result of evolution. Our model may then be viewed as a generalization of the classic theory where an implicit assumption of the latter is turned into a prediction.

Both cognitive impairment and cardiovascular diseases have a high incidence in the elderly population, increasing the burden of care and reducing the quality of life. Studies have suggested that cognitive impairment interacts with cardiovascular diseases such as coronary heart disease, abnormal blood pressure, heart failure, and arrhythmia.

On one hand, cognitive impairment in the elderly influences the progression and self-management of cardiovascular diseases and increases the risk of cardiovascular-related adverse events. On the other hand, coronary heart disease, heart failure, higher blood pressure variability, orthostatic hypotension, and atrial fibrillation may aggravate cognitive impairment. The role of blood pressure levels on cognition remains controversial.

Several shared biological pathways have been proposed as the underlying mechanism for the association. Cardiovascular diseases may lead to cognitive decline even dementia through cerebral perfusion damage, brain structural changes, inflammation, β-amyloid deposition, and neuroendocrine disorders. It is of great significance to study the interaction and put forward effective interventions in an overall perspective to reduce care burden and improve the quality of life of the elderly patients.

It's no secret that physical activity is associated with a lower risk of cardiovascular disease and a longer life, irrespective of gender and ethnicity, with the benefits accruing in tandem with the effort expended. But relatively few studies have looked exclusively at whether exercise in later life can help ward off heart disease and stroke in old age. To plug this knowledge gap, researchers drew on data from the Progetto Veneto Anziani (ProVA), a study of 3099 older Italians, age 65 and above.

Participants filled in questionnaires on their physical activity levels at each of the time points. Moderate physical activity included walking, bowls, and fishing, while vigorous physical activity included gardening, gym work-outs, cycling, dancing, and swimming. Those whose physical activity added up to 20 or more minutes a day were defined as active; those who clocked up less than this were defined as inactive. Men were more likely to be physically active than women.

During the monitoring period, 1037 new diagnoses of heart disease, heart failure, and stroke were made. Increasing levels of physical activity as well as maintaining an active lifestyle over time were associated with lower risks of cardiovascular disease and death in both men and women. Patterns of stable-high physical activity were associated with a significantly (52%) lower risk of cardiovascular disease among men compared with those with stable-low patterns. The greatest benefits seemed to occur at the age of 70. Risk was only marginally lower at the age of 75, and no lower at the age of 80-85, suggesting that improving physical activity earlier in old age might have the most impact, say the researchers.

It is not easy in the present environment for endocrinologists to avoid being drawn, however reluctantly, into testosterone misuse. Many endocrinologists are referred patients with a single, marginally low blood testosterone measurement seeking testosterone treatment for "hypogonadism". Under the misguidance of numerous extant guidelines or other manifestos, encourage excessive testosterone prescribing where there is any clinical doubt, which is almost always. They may fear that if they do not succumb to prescribing on demand, the patient will go doctor shopping and get the testosterone they think they need or demand elsewhere. These dilemmas are enlivened, if not enlightened, by concerted marketing and papers emanating from pharma, upscale single-issue men's health clinics, and academic enthusiasts. These rarely highlight the vested commercial interests, where present, promoting testosterone use outside approved indications under the disease-mongering rubric of "hypogonadism".

Testosterone is unique among hormones for its high level of public recognition, which unfortunately is imbued with fantasies and fictions unrelated to endocrine reality, an enchantment that easily unlocks latent but irrational wishes for rejuvenation. Reproductive medicine is unique in that, unlike other medical specialties, virtually everyone's personal experience of sex and reproduction provides them with the subjective confidence they possess sound insight into reproductive biology and medicine without needing recourse to the established objective facts. This particularly extends to beliefs about what testosterone is and does biologically. This illusion of sophisticated expertise forms a powerful coupling with tenacious wishful thinking. This latent demand is readily entrained by clever marketing from pharma and other commercial enterprises that promotes testosterone's use as an anti-ageing or sexual dysfunction tonic.

Testosterone prescribing for men without pathological hypogonadism is a therapeutic illusion in search of a definition. It is fostered by wishful thinking of an affluent populace with eyes mistily focused on the mirage of rejuvenation. The public health consequences of the recent epidemic-like increase in testosterone prescribing on cardiovascular and prostate health and iatrogenic androgen dependence remain to be evaluated over coming decades. At best it may have little adverse impact but there could be detrimental changes in cardiovascular and/or prostate health. Some evidence suggests that significant numbers of men who start testosterone treatment may have difficulty stopping it even if it proves ineffective as they become androgen dependent from androgen deficiency withdrawal symptoms while their endogenous testosterone production resumes, albeit slowly.

Until recently, it was believed that the immune system was mostly dormant unless the body was under attack in connection with infections. However, it now turns out that the immune system most likely also plays an important role for perfectly healthy people and can affect the body's production of vital energy sources. Specifically, the immune system causes the liver of the healthy body to produce an energy source called ketone bodies. This takes place by letting the liver burn fat during fasting.

When we're fasting - that is, we haven't eaten anything for maybe half a day or a full day - we start drawing on our fat deposits, but not all of our body cells are capable of burning fat. This applies, among other things, to the brain, which instead depends on the production of ketone bodies, which the liver forms by metabolising fats. The ketone bodies thereby energise the body, allowing us to function even if we don't eat anything.

Ketone bodies are also the focal point of many popular weight loss diets focusing on cutting carbohydrates from our food, so the body begins burning fat instead. Other research also suggests that the ketone bodies may have a positive impact on, among other things, risk factors for the development of cardiovascular disease. Researchers now believe that the immune system affects the production of ketone bodies in fit and healthy individuals and given the beneficial effects of ketone bodies in various common metabolic disorders, this knowledge can hopefully also be applied to understand how the immune system is trying to keep the body in equilibrium when we're sick.

The accumulation of damaged/senescent cells in the body with time is a hallmark of aging. These cells are believed to play a key role in the onset and/or progression of various aging-associated diseases. More generally, the decreased regenerative ability of transplanted stem cells in older recipients may also be partly attributable to the presence of a high level of senescent cells.

Many factors produced by senescent cells - including proinflammatory cytokines, profibrotic molecules, and damaging agents such as labile iron and reactive aldehydes - are known to disrupt the function of normal cells and cause organ function to decline. The hostile environment created by senescent cells is likely to impair the ability of transplanted stem cells to home in on target tissues, mature, and restore tissue function. Therefore, prior removal of senescent cells will likely enhance the effectiveness of stem cell transplantation therapies.

In recent years, two major observations in the longevity field have been made: (a) The use of senolytics to remove senescent cells significantly improved health and lifespan in mice and as might be expected, this approach enhanced the repopulation ability of endogenous stem cells (b) stem cell transplantation has demonstrated beneficial effects in reducing aging-associated functional decline in both mice and humans, and extended lifespans in mice. Our SenoStem project will test the hypothesis that prior removal of senescent cells by senolytics will create a more favorable niche for stem cells to engraft, and thus enhance their regenerative effect in older recipients. The overall aim is to determine whether these two different lifespan-extending interventions can act synergistically.

Altos Labs has signed up a dream team of scientists, numerous Nobel laureates among them. They will start work in the spring at two labs in the US and one in the UK, with substantial input from researchers in Japan. Their aim is to rejuvenate human cells, not with an eye on immortality - as some reports have claimed - but to stave off the diseases of old age that inexorably drive us to the grave. "This is not about developing the first 1,000-year-old human; it's about ensuring old age is enjoyed and not endured. Who wants to extend lifespan if all that means is another 30 years of ill health? This is about increasing healthspan, not lifespan."

Phrases such as "solving ageing" and "solving death" are seen as wrong-headed. "Apart from being silly at the moment, it raises all kinds of societal issues. I think it's morally dubious. Huge things would percolate through society with a substantial increase in life expectancy brought about by human intervention. We're living longer and longer already. People are suffering from disability and loss of quality of life because of ageing. That's what we should be trying to fix. We should be trying to keep people healthier for longer before they drop off the perch. Stay healthy then drop dead, die in your sleep. I think that's what most people want."

Immune processes can become out of balance in the elderly, leading to persistent low-grade inflammation. It is thought that those with long-lasting low-grade inflammation have reduced responses to pathogens and carcinogenesis, and are more prone to autoimmunity. This would render them more vulnerable to developing age-related diseases and becoming frail. In addition to ageing, a potential driver of chronic low-grade inflammation could be the amount of body fat, since adipocytes can activate the immune system directly.

It is still largely unknown when and how low-grade inflammation develops in the course of ageing, and how this is related to frailty. The few longitudinal studies on this subject showed that in frail people, often low-grade inflammation was present over a long period of time. In most studies, including our own, the presence of chronic low-grade inflammation was assessed by measuring the plasma concentrations of only one or two inflammatory markers, notably CRP and IL-6. However, inflammation is a complex process in which many proteins are involved. Some studies already suggested that looking at a larger panel of inflammatory biomarkers, including a broader range of (chemotactic) cytokines, would improve the understanding of the relationship between low-grade inflammation and age-related diseases.

In order to gain more insight into how long-lasting low-grade inflammation relates to frailty, and taking into account sex differences, we performed an exploratory study using data and blood samples from a selection of participants (n = 144) in the longitudinal Doetinchem Cohort Study. Blood samples and data were collected at 5-year intervals covering a period of approximately 20 years.

IFN-γ-related markers and platelet activation markers were found to change in synchrony. Chronically elevated levels of IL-6 pathway markers, such as CRP and IL-6R, were associated with more frailty, poorer lung function, and reduced physical strength. Being overweight was a possible driver of these associations. More and stronger associations were detected in women, such as a relation between increasing CD14 levels and frailty, indicating a possible role for monocyte overactivation. In conclusion, as BMI and waist circumference are related to elevations of immune markers in the IL-6 pathway, chronic inflammation might be an important mediator of the relationship between BMI and frailty.

Researchers looked at the role of age and physical training in maintaining fat tissue function. Specifically, they studied mitochondria, the tiny power plants within fat cells. Mitochondria convert calories from food to supply cells with energy. To maintain the life processes within cells, they need to function optimally. The researchers compared mitochondrial performance across a range of young and older untrained, moderately trained and highly exercise trained men. The results demonstrate that the ability of mitochondria to respire - i.e., produce energy - decreases with age, regardless of how much a person exercises. "Although mitochondrial function decreases with age, we can see that a high level of lifelong exercise exerts a powerful compensatory effect. In the group of well-trained older men, fat cells are able to respire more than twice as much as in untrained older men."

Just as a car engine produces waste when converting chemical to usable energy, so do mitochondria. Mitochondrial waste comes in the form of oxygen free radicals, known as ROS (Reactive Oxygen Species). ROS that isn't eliminated damages cells and the current theory is that elevated ROS can lead to a wide range of diseases including cancer, diabetes, cardiovascular disease, and Alzheimer's. Therefore, the regulation of ROS is important.

The group of older people who train most form less ROS and maintain functionality to eliminate it. Indeed, their mitochondria are better at managing waste produced in fat cells, which results in less damage. Therefore, exercise has a large effect on maintaining the health of fat tissue, and thereby probably keeping certain diseases at bay as well. The researchers can also see that the older participants who exercised most throughout life have more mitochondria, allowing for more respiration and, among other things, an ability to release more of the fat-related hormones important for the body's energy balance.

Blood type is determined by the presence of antigens on the surface of red blood cells - type A blood has the A antigen, type B has the B antigen, type AB blood has both antigens and type O has none. Antigens can trigger an immune response if they are foreign to our bodies. That is why for blood transfusions we can only receive blood from donors with the same blood type as ours, or universal type O. Likewise, antigens A and B are present on the surfaces of blood vessels in the body, including vessels in solid organs. If someone who is type O (meaning they have anti-A and anti-B antibodies in their bloodstream) received an organ from a type A donor, for example, the organ in all likelihood would be rejected. Consequently, donor organs are matched to potential recipients in the waitlist based on blood type, among other criteria.

This proof-of-concept study used the Ex Vivo Lung Perfusion (EVLP) system pioneered as a platform for the treatment. The EVLP system pumps nourishing fluids through organs, enabling them to be warmed to body temperature, so that they can be repaired and improved before transplantation. Human donor lungs not suitable for transplantation from type A donors were put in the EVLP circuit. One lung was treated with a group of enzymes to clear the antigens from the surface of the organ, while the other lung, from the same donor, remained untreated. The team then tested each of the lungs by adding type O blood (with high concentrations of anti-A antibodies) to the circuit, to simulate an ABO-incompatible transplant. The results demonstrated that the treated lungs were well tolerated while the untreated ones showed signs of rejection.