Fight Aging!

The field of aging research has always been more interested in changes in gene expression that can be connected to age-related decline and disease than in deeper causes of aging that might be behind those gene expression changes. Altered gene expression is driven by epigenetics. Epigenetic regulatory systems, such as DNA methylation of sites on the genome, alter the pace at which specific proteins are manufactured from their genetic blueprints. Epigenomic alterations are dynamic, responsive to the environment and changes in cell state. It is a highly complex system, understood at the high level, but far from completely mapped in all of its fine details.

Two technologies have led to a greatly increased interest in the epigenetics of aging. Firstly, there are the epigenetic clocks, produced by analysis of epigenomic data in search of patterns that correlate with age. These clocks show a strong correlation with chronological age, as well as some ability to reflect biological age, in that a higher clock age than chronological age indicates an increased risk of mortality and age-related disease. Secondly, reprogramming cells via exposure to Yamanaka factors not only produces induced pluripotent stem cells, but also reverses a sizable fraction of age-related epigenetic change. Even partial reprogramming, a short exposure to reprogramming factors insufficient to change a somatic cell into a stem cell, produces this epigenetic rejuvenation.

The hope here is that there is a path to both a class of rejuvenation therapies that force cells in aged tissues into more youthful behavior, as well as tools that can rapidly assess the performance of any rejuvenation therapy via its effect on epigenetic patterns. While the path such reprogramming therapies could be rapid given a healthy appetite for risk, a great deal of work remains on the more conservative, usual road to clinical development and adoption. Large-scale funding is now devoted to this path, given the advent of Altos Labs, and we shall have to see how it progresses.

How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span

As of the year 2021, aging is considered both an intriguing process that research attempts to understand and a universal burden that the scientific community and the industry seek to intervene with. Currently, various theories have been put forward as to how we age, which physical alterations occur during aging and how we could substantially increase healthy life span or even maximal life span. In 2013, a comprehensive review proposed a detailed framework incorporating nine hallmarks of aging to characterize this complex process. These hallmarks comprise epigenetic alterations, telomere attrition, genomic instability, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, deregulated nutrient sensing, and altered intercellular communication. Intriguingly, these attributes are highly interconnected. Here, we will focus on age-related epigenetic alterations and how targeting the epigenetic landscape might enable extension of life span.

Underlying epigenetic mechanisms such as histone modifications and DNA methylation were discovered at the end of the 20th century and now have a well-established role in the regulation of gene expression. In general, histones are bound to DNA in order to compact it to accommodate the size of the nucleus. This DNA-histone interaction is dynamic. The modifications of the tail domain of histones by small molecules can alter the interaction between the DNA and histone thus changing the accessibility of that specific genomic area.

Here, we present recent findings on epigenetic changes involving histone modifications and DNA methylation during aging and age-associated maladies such as neurodegeneration and cancer. In this regard, we also outline the emergence of DNA methylation clocks to determine biological aging. We will cover the utility of epigenetic signatures as biomarkers and the physiological implications of respective alterations. Age-associated metabolic dysregulation, which could underlie epigenetic changes, and other risk factors for age acceleration, will be described before we finally explore therapeutic interventions aiming to prevent age-associated maladies and to increase healthy life span including the emerging field of cellular reprogramming.

One of the potential side effects of there now being a very sizable amount of funding devoted to realizing therapies based on in vivo partial reprogramming of cells is an increase in the quality of popular press articles about the treatment of aging as a medical condition. We can hope that journalists become a touch more careful and considered when it comes to a field in which billions in funding are now flowing towards research and development. The bar is of course quite low in the matter of journalism and the science of aging, but improvement is always welcome.

The latest exploration into longevity research is 'controlled reprogramming', specifically of our epigenome. The term 'epigenome' is derived from 'epi', the Greek for 'above', and describes chemical changes to our DNA and DNA-associated proteins. These changes are responsible for altering gene expression patterns, but do not affect the underlying DNA sequence. This explains why cells in our body can have distinct properties and functions, despite containing identical genes. Epigenetic changes can also explain ageing (or so it is hoped), hence reversing epigenetic changes may be the key to reversing ageing altogether.

The basis of controlled reprogramming relies on Yamanaka factors - four transcription factors that can be used to remodel the epigenome of a differentiated cell, such as a skin cell, and return it to an undifferentiated state. Ten years after Shinya Yamanaka received the Nobel prize for his discovery of these eponymous factors, a Silicon Valley startup, Altos Labs, has placed a three billion-dollar bet on the ability of three of these factors to reverse ageing.

Will their bet pay off? Author and scientist Andrew Steele remain unconvinced. Whilst Steele does not doubt that we will see anti-ageing treatments in the near future, he is hesitant to name Altos Labs as their source. He described the ten hallmarks of the ageing process, of which epigenetic changes are only one. Other hallmarks include the accumulation of senescent cells and the shortening of telomeres, caps on the end of our chromosomes that are degraded each time a cell divides. The net result of all these hallmarks, including epigenetic modifications, is the manifestation of ageing in the form of cancer, heart disease, wrinkles, memory loss, diabetes, and general decline. The premise that three simple transcription factors, the Yamanaka factors, could prevent all this suffering might just be too good to be true.

There are examples of age-related changes that can't necessarily be reversed by controlled reprogramming. One example is collagen, an extremely long-lived protein that is replaced very slowly, if at all. Collagen and similar proteins form an extracellular matrix that is vital for maintaining the integrity of nearby cells. Rejuvenating these cells without repairing the extracellular matrix would leave cells unsupported, proving a futile effort. "If reprogramming works, it might be that other treatments are needed in combination with it to realise its true potential, and it would be a great shame if we've failed to develop them in the meantime."

Link: https://www.varsity.co.uk/science/23088

In one sense, genes absolutely determine longevity. That is the case when we look at differences in species life span. Those differences have their origin in the genome. In another sense genes do not seem to be all that important, when it comes longevity differences within a species. The more that researchers dig into growing vaults of genomic data, the lower their estimated contribution of genetic variants to human life expectancy becomes. Cultural and lifestyle choice differences appear to be a much better explanation for human lineages exhibiting exceptional longevity than inherited genetic variants.

Aging is a complex process indicated by low energy levels, declined physiological activity, stress induced loss of homeostasis leading to the risk of diseases and mortality. Recent developments in medical sciences and an increased availability of nutritional requirements has significantly increased the average human lifespan worldwide. Several environmental and physiological factors contribute to the aging process. However, about 40% human life expectancy is inherited among generations, many lifespan associated genes, genetic mechanisms and pathways have been demonstrated during last decades.

In the present review, we have evaluated many human genes and their non-human orthologs established for their role in the regulation of lifespan. The study has included more than fifty genes reported in the literature for their contributions to the longevity of life. Intact genomic DNA is essential for the life activities at the level of cell, tissue, and organ. Nucleic acids are vulnerable to oxidative stress, chemotherapies, and exposure to radiations. Efficient DNA repair mechanisms are essential for the maintenance of genomic integrity, damaged DNA is not replicated and transferred to next generations rather the presence of deleterious DNA initiates signaling cascades leading to the cell cycle arrest or apoptosis. DNA modifications, DNA methylation, histone methylation, histone acetylation, and DNA damage can eventually lead towards apoptosis.

Currently, research on the contribution of genes to the aging process, cellular stability, and longevity of lifespan is at initial stages. The data available is scattered, and the individual reports provide information about the contribution of selected either a gene or a group of similar genes and genetic mechanisms in the regulation of aging and lifespan. Further studies for the identification of potential genetic targets to protect against aging-associated diseases are also required. Finally, the translation of these genetic findings into clinical practice poses a big challenge.

Link: https://doi.org/10.3390/ijms23031499

Senescent cells accumulate with age, a growing imbalance between pace of creation and pace of clearance. The majority of senescent cells come into being as cells reach the Hayflick limit on replication, and survive for only a short time before succumbing to programmed cell death or immune system activity. But senescent cells can be created by injury, inflammation, and other forms of damage as well. Senescent cells secrete pro-growth, inflammatory signals. This is useful in the short term as a way to help the body clear up damage or potentially cancerous cells, but when sustained over the long term it is highly disruptive to tissue function.

A range of research in recent years strongly implicates cellular senescence in age-related kidney dysfunction. There is good evidence for removal of senescent cells to reverse kidney disease. Kidney function is so profoundly vital to health that its loss is damaging to other organs throughout the body, including heart, blood vessels, and brain. Kidney decline alone can drive a systemic fall into more ever more rapid dysfunction and rising mortality in later life, and senescent cells appear to be driving a great deal of this process. In today's open access research materials, researchers discuss the interaction between GSK3β overexpression and cellular senescence in the aging kidney. Suppressing GSK3β expression reduces markers of cellular senescence in the kidney and slows the age-related loss of kidney function. Whether this is a better approach than current attempts to build senolytic therapies that can selectively destroy senescent cells remains to be seen.

GSK3β and the aging kidney

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.

Age-related GSK3β overexpression drives podocyte senescence and glomerular aging

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.

The publicity materials here discuss an intriguing approach to reducing the issues of rejection associated with organ transplantation. Some of the underlying mechanisms relate to incompatible blood types. It is possible to perfuse an extracted organ with enzymes that convert the biochemistry associated with blood type to blood type O, which is compatible with other types. The result is an organ that can be transplanted with greater safety.

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.

Link: https://www.uhn.ca/corporate/News/Pages/Creating_universal_blood-type_organs_for_transplant.aspx

Mitochondria are effectively power plants, hundreds of them working in every cell to produce chemical energy store molecules to power cellular processes. Mitochondrial function declines with age, unfortunately, for underlying reasons that appear to involve gene expression changes that reduce the effectiveness of mitochondrial quality control mechanisms. This has profound effects on tissue function throughout the body, and is an important contribution to degenerative aging. Here, researchers discuss some of the effects on fat tissue specifically.

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.

Link: https://science.ku.dk/english/press/news/2022/well-functioning-fat-may-be-the-key-to-fewer-old-age-ailments/

While research never ends, more than enough is known about the mechanisms of aging to develop therapies that can potentially slow or reverse facets of aging. That said, establishing that a mechanism exists is one thing, but determining how important that mechanism is to aging or any specific age-related disease is quite another. Cellular metabolism is enormously complex and incompletely mapped. It is impossible to theorize effectively on whether mechanism A causes more dysfunction than mechanism B. In many cases it is even hard to comment on the degree to which mechanism A causes mechanism B, or vice versa.

There is a definitive, best way to figure out the importance of a mechanism: remove it, in isolation of all other aspects of aging. Unfortunately there is only one mechanism of aging for which that can be achieved at present, the presence of senescent cells, which can be destroyed by senolytic therapies. Thus we now know a great deal about how important cellular senescence is to aging and specific age-related diseases, in mice at least. But all of the other approaches to slowing aging, such as the well-studied practice of calorie restriction, change many mechanisms and tell us little about relative importance. If developing therapies to target the mechanisms of aging, we need a way to measure their outcome rapidly. If every potential approach must be laboriously run through life span studies in mice, or equally lengthy and costly experiments, then progress will necessarily be slow. Even focusing funding and researchers on approaches that are better rather than worse will take far too long.

The most promising work when it comes to rapid assessment of aging is the production of epigenetic clocks. Some of the epigenetic marks on the genome change in characteristic ways with age, and evidence shows that accelerated epigenetic aging tends to correlate with a greater mortality and disease risk. But no-one yet understands how these epigenetic changes connect to the underlying mechanisms of aging. Thus without calibrating a specific clock against a specific therapy in life span studies, in mice at least, one can't say whether or not the results are real and meaningful. In order to use clocks to rapidly assess new therapies that potentially slow or reverse aging, the clocks must be understood. Today's open access paper is an example of the first steps in that direction, but a great deal more work is needed.

Clock Work: Deconstructing the Epigenetic Clock Signals in Aging, Disease, and Reprogramming

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.

Evidence increasingly points to chronic inflammation as an important contributing cause of age-related frailty. The immune system becomes increasingly dysfunctional with age, more so in some people than in others, for a range of causes. A part of that dysfunction is overactivation in response to issues such as a growing burden of senescent cells, molecular damage, and metabolic waste, as well as excess visceral fat and changes in the gut microbiome that lead to greater populations of inflammatory microbes. Inflammatory signaling throughout the body disrupts tissue maintenance, particularly that required for muscles. Physical weakness follows as this environment of dysfunction is sustained for years, causing loss of muscle mass and strength.

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.

Link: https://doi.org/10.1002/cti2.1374

When various talking heads unite to tell us that the longevity industry isn't actually working to extend human life span, and it is all about letting you die at the usual time with less arthritis and pain, I'm not entirely sure who they think needs to be reassured in this way. The character of the powers that be, in the English language world anyway, appears to be that they are terrified of all possible change, and project that fear onto the populace. Their propaganda follows that apparent view. Under the hood, from person to person, who knows why they think it is necessary to toe the current party line that work on the mechanisms of aging will not lengthen life spans. It continues to puzzle me.

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."

Link: https://www.theguardian.com/science/2022/feb/17/if-they-could-turn-back-time-how-tech-billionaires-are-trying-to-reverse-the-ageing-process

Researchers here discuss what is know of mechanisms surrounding telomere shortening in old tissues. Telomeres are the caps of repeated DNA at the ends of chromosomes. Their length is reduced a little with each cell division, and when too short, cells become senescent or self-destruct. This acts as a part of the limiting mechanisms that prevent normal somatic cells from dividing indefinitely, the Hayflick limit that ensures turnover of cells in tissues. Stem cells can continue to replicate and produce replacement daughter somatic cells with long telomeres via use of telomerase to lengthen their telomeres.

The body is thus divided into a small set of privileged cells and the majority of limited cells, a way in which evolution keeps cancer risk low enough for species survival. Average telomere length is shorter in older tissues arguably primarily because stem cell activity is lowered, and thus fewer replacements with long telomeres are introduced.

The above is a perhaps overly simplistic overview at the high level. The reality on the ground when cells begin to exhibit shorter telomeres is, as is usually the case in cellular biochemistry, much more complicated. Today's open access paper discusses some of the details. This is relevant to older tissues in which many more cells than is the case in young tissues are close to the Hayflick limit. There will be dysfunction that is more subtle than simply an increase in senescent cell creation.

Telomere dysfunction in ageing and age-related diseases

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.

In their latest newsletter, the SENS Research Foundation leadership noted one of their more recent programs, focused on identifying synergies between senolytic therapies to remove senescent cells and stem cell therapies intended to augment regeneration. It is possible that senolytic treatment could help make the aged tissue environment less hostile, enabling transplanted cells to better aid regeneration and tissue maintenance. This is a comparatively straightforward hypothesis to test in animal studies: all of the necessary tools already exist, and just need to be combined. Finding an improvement would likely speed the adoption of first generation senolytic therapies, such as the dasatinib and quercetin combination, by encouraging their use in the sizable stem cell medicine community.

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.

Link: https://www.sens.org/exploring-synergies-between-senolysis-and-stem-cell-therapy/

The immune system doesn't just chase down pathogens and destroy errant cells. It is also involved in regeneration, tissue maintenance, the workings of synaptic connections in the brain, and many other processes. When the immune system runs down with age, becoming overly inflammatory and less competent. This is disruptive of many processes. The research here should be viewed in that context; if the immune system is involved in health-related metabolic adaptations to dietary intake, how does that interaction run awry with age?

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.

Link: https://www.sdu.dk/en/om_sdu/fakulteterne/naturvidenskab/nyheder-2022/sund_krop_og_immunforsvar

Stem cell therapies, and cell therapies in general, have tremendous promise in treating age-related conditions, particularly those that lead to structural damage in the body, such as degenerative disc disease. While animal studies have produced very interesting results, these therapies have yet to achieve more than initial goals in clinical practice, however. Hematopoietic stem cell transplants work well for the uses they are put to, albeit while being a comparatively stressful, higher risk procedure. Immunotherapies based on cell transplants are quite well advanced in the cancer field. First generation mesenchymal stem cell transplants are quite good at suppressing chronic inflammation for a time, but increased regeneration is an unreliable outcome at best. In general, regeneration through cell therapy remains an elusive goal in the clinic.

In part, this is likely because it is hard to manage cells in culture. Small differences in implementation of a protocol for sourcing and growing cells used in therapy can cause large differences in the quality of the cells. Two clinicians performing the same work, with the same protocol, in different clinics may produce widely varying outcomes for patients. This has been very evident in the delivery of mesenchymal stem cell therapies.

Beyond first generation therapies, delivery of cells that are more specialized to the target tissue has produced promising results in animal studies. Thymic regrowth can be engineered by injection of suitable cells, while numerous different approaches to delivering cardiomyocyte cells or their progenitors have produced heart regeneration. Clinical trials of numerous varieties of the more sophisticated forms of cell therapy have been undertaken. Certainly, cell therapies in animals have produced good results in models of disc degeneration. But it seems there is a way to go yet before this sort of therapy is widely used in the clinic. The regulators make stringent quality and reliability demands on developers, and these are not easy goals to reach at present.

Application of stem cells in the repair of intervertebral disc degeneration

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.

This cutting opinion piece is written in opposition to the prevalence of testosterone therapy, offered in many cases with the (dubious) promise of it being a way to push back the advance of aging. Hormone therapies in general are not to be taken lightly, but are widely used. Anyone should be free to try whatever they feel may work for them, but this approach may not be justified for most people given the balance of risk and benefit. That isn't a justification for restriction of personal freedom, but rather for greater efforts to educate in the face of overly enthusiastic marketing.

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.

Link: https://doi.org/10.3389/fendo.2021.682620

There is plenty of evidence for moderate levels of exercise in late life to lower cardiovascular disease risk. When it comes to age-related disease, exercise remains better than most medicine for most people, a sad state of affairs that will hopefully change given technological progress in the years ahead. The study here offers yet another example of epidemiological data that supports the benefits of exercise in old age.

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.

Link: https://www.eurekalert.org/news-releases/943080

The gut microbiome changes with age. The complex balance of microbial species shifts in an unfavorable direction, and with it comes ever greater chronic inflammation alongside a loss of beneficial metabolite production. It remains an open question as to how much of the inflammation of aging, disruptive of tissue function and health, is caused by the gut microbiome. Identifying mechanisms is one thing, figuring out their relative importance quite another. The only practical way to achieve that goal is to change just the one mechanism in isolation of all the others, and observe the results.

In the case of the aging gut microbiome, there are a few comparatively simple approaches demonstrated to reverse age-related changes for a protracted period of time. The most proven is fecal microbiota transplantation from a young individual to an old individual. In short-lived species, this resets the microbiome, improves health, and extends life. It is not an approved human therapy in the US, but is nonetheless often used for treatment of conditions in which pathological bacteria overtake the intestines, both by physicians, and by patients taking matters into their own hands. Setting aside the question of how to screen for microbes that might cause issues to an older individual, it is a simple procedure.

At some point the clinical community will get around to running formal trials of fecal microbiota transplantation as a means to improve health in later life, but since intellectual property will likely be hard to produce and defend for this type of therapy, we shouldn't hold our breath waiting for that to happen. Progress, and funding for small-scale trials, is more likely to emerge from philanthropic initiatives. Initiatives of this sort have yet to exist for this approach to aging, unfortunately.

The Potential Role of Gut Microbiota in Alzheimer's Disease: From Diagnosis to Treatment

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.

Cognitive impairment and cardiovascular disease can have a bidirectional relationship, but much of the attention tends to focus on how cardiovascular aging can cause dysfunction in brain tissue. Mechanisms involved include a declining supply of nutrients to the brain, the rupture of small blood vessels due to hypertension, leakage of the blood-brain barrier that provokes neuroinflammation, and so forth. In principle, cognitive impairment can aggravate the situation via reduced the level of exercise, degree to which medical care is utilized, and so forth, making cardiovascular aging worse, and so the cycle progresses. Picking apart specific contributions and assigning relative importance to them remains challenging, however.

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.

Link: https://doi.org/10.1177/20406223211063020

The present consensus on the evolution of aging is that selection pressure is lower in late life, inevitably, because there is always greater advantage to early life reproduction in an environment of hazards and predation. Thus species will evolve bodily systems that work well in early life, but fail over time, because mutations that provide early life benefit will be selected even when they cause later harm and decline. That said, researchers here produce models to suggest that the arrow of causation runs the other way, that evolution will simply produce lowered late-life selection regardless. As in all evolutionary modeling, this might be taken with a grain of salt for now, and treated as an interesting idea for discussion only; the field generates a great deal of hypotheses based on modeling and little else.

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.

Link: https://doi.org/10.1038/s41467-022-28254-3

A few proteins in the body are capable of misfolding or becoming otherwise altered in ways that encourage other molecules of the same protein to do the same. They can spread throughout a tissue and the body, given time, forming aggregates that precipitate into solid clumps and fibrils, surrounded by a halo of toxic biochemistry that harms cells. This is an age-related problem, likely because the systems of maintenance and recycling responsible for clearing aggregates falter with age, a victim of rising levels of molecular damage and the maladaptive reactions to that damage.

Amyloid-β, associated with Alzheimer's disease, is likely the most well studied of the amyloids, with transthyretin amyloid a close second. In the case of amyloid-β, immunotherapies have proven themselves capable of clearing this molecular waste, though without achieving patient benefits as a result. For transthyretin amyloid, existing therapies slow the aggregation process. A few other approaches that clear existing aggregates are in development but either stalled (CPHPC) or not moving forward as fast as we'd like (catabodies).

In today's open access paper, researchers discuss disaggregases as a basis for the clearance of amyloids. Disaggregases are a broad class of molecules capable of breaking apart amyloid aggregates. Some exist in the human body, well known parts of cellular stress response systems, some might be mined from other species. It is an interesting topic, and not that well explored as an approach to anti-amyloid therapies.

Molecular mechanisms of amyloid disaggregation

Cellular deregulation of amyloid formation is implicated in many neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease (PrD), and diseases affecting other parts of the body such as cataracts, Type II Diabetes, and Corneal Dystrophy (CD). Fifty different proteins or peptides involved in such amyloid aggregation disorders are structurally and functionally characterized. Typically amyloid fibrils are generated from highly amyloidogenic peptide regions of a protein as the result of protein misfolding, genetic mutations, or undesired proteolytic cleavage of that protein.

However, not all amyloid fibril formation results in detrimental diseases while some may be important to fulfil a biological function and take place in well-modulated and highly contingent condition. In some cases, functional amyloids are controlled by a balance between peptide production and clearance of amyloids, reduction in the production of oligomeric seeds, minimizing interaction of oligomeric seeds with other aggregation-prone proteins via compartmentalization and the presence of an inherent disaggregation mechanism. Understanding why certain amyloids are toxic while others are biologically important may reveal important information on the function of these amyloids or develop novel treatment avenues in amyloid associated diseases.

In order to remove toxic amyloid build-up in the cell during cellular stress, some protozoans such as yeasts are equipped with molecular machines capable of disaggregating diverse amyloid and nonamyloid structures. In yeast, several types of heat shock proteins (HSPs) are discovered to work together to form disaggregation machinery. This machinery reduces the toxic amyloid species present in the cell and restores the native function of the protein buried in the amyloids via an amyloid disaggregation process. Metazoans such as mammals might experience less cellular stress resulting in the rapid build-up of toxic amyloid in the intracellular environment but are susceptible to accumulation of both intracellular and extracellular amyloids in various pathological conditions. To disaggregate these toxic amyloids in the extracellular environment, metazoans are equipped with ATP-independent chaperones such as HtrA1 and L-PGDS instead of the ATP-dependent HSPs, found in yeast. To deal with intracellular amyloids, the metazoan cells are also equipped with other types of HSPs i.e., Hsp110, Hsp70, Hsp40, and other smaller proteins from the heat shock protein families. These diverse disaggregation mechanisms evolved to reverse the formation of the toxic amyloids and survive through cellular stress and preclude amyloid-related pathogenicity.

In neurodegenerative diseases such as Alzheimer's disease, aggregates resulting from amyloidogenic peptides deposit into senile plaques which later leads to neurofibrillary tangles, synaptic dysfunction, and neuronal cell death. In each disease, a specific peptide or protein aggregates to form amyloid fibrils. There is no effective therapeutic solution that is capable of reversing the formation of these aggregates. Amyloid disaggregation seems to be a viable option where these amyloid fibrils can be broken down into non-toxic aggregates and this would possibly help to mitigate the toxic effects caused by these amyloid fibrils. In this review, we mainly focus of the disaggregation and the remodulation of the preformed fibrils into smaller molecular weight species by different disaggregating agents instead of the inhibition of fibril formation or aggregation. Many protein disaggregases have shown promising results in in vitro studies where pathogenic amyloids fibrils are solubilized through the action of these disaggregases. These studies will be discussed in this review to showcase the potential of using amyloid disaggregation as a treatment for several neurodegenerative diseases.

Calcification of tissues is a feature of aging, and problematic in blood vessels and heart tissue. It reduces elasticity and cardiovascular tissue function, leading to eventually fatal problems. The underlying mechanisms that drive calcification likely involve the inflammatory signaling produced by senescent cells, contributing to the shift in behavior that makes cells in blood vessel walls act more like osteoblasts, attempting to build bone by depositing calcium structures in the tissue. As noted here, the roots of calcification remain much debated, and there is plenty of room for new discoveries.

Vascular calcification (VC) is a prominent clinical pathology of atherosclerosis, diabetes mellitus, hypertension, aging, and chronic kidney disease (CKD), resulting in abnormal calcium phosphate accumulation in the intimal and medial layers of the vessel wall. After vascular calcification, the stiffness of the vascular wall is increased, and the compliance is decreased, which results in myocardial ischemia, left ventricular hypertrophy, and heart failure. At present, vascular calcification is still lacks effective treatment methods, and the pathogenesis mechanism remains unclear.

The phenotype switching of vascular smooth muscle cells (VSMCs) has been regarded as the principal driver in the calcification of intimal and medial layers. VSMCs undergo the phenotypic transformation from a differentiated "contractile" into a dedifferentiated "synthetic" proliferative phenotype in the process of vascular calcification. The phenotypic switching VSMCs express higher osteoblast-like markers, and is associated with increased proliferation and migration ability. The osteoblast-like phenotype of VSMCs is regarded as the cellular characteristic factor of vascular calcification. Many factors such as oxidative stress damage, hyperphosphatemic environment, and inflammation increase the indices related to bone formation in VSMCs and promote their transformation into osteoblasts. On the other hand, a variety of biochemical factors are also involved in the phenotype switching of VSMCs.

Matrix vesicles (MVs), one kind of extracellular matrix derived extracellular vesicles (EVs), are membrane-bound microparticles released by cells, containing various cargo, including proteins, carbohydrates, lipids, DNA and small RNAs, such as microRNAs (miRNAs). The origin and composition of MVs determine their calcification potential. Recent evidence showed that extracellular MVs serve as nucleating foci to initiate microcalcification. The formation and secretion of MVs and the increase of intracellular alkaline phosphatase (ALP) activity are also involved in the osteoblast-like phenotype transformation of VSMCs.

However, the specific mechanisms and functions of MVs regulating vascular calcification have not been fully elucidated. For example, what is the originating cell that releases MVs in vascular calcification, and how do the pro-calcification MVs get into the recipient cell? This article aims to review the detailed role of MVs in the progression of VC and compare the difference with other major drivers of calcification, including aging, uremia, mechanical stress, oxidative stress, and inflammation. We will also bring attention to the novel findings in the isolation and characterization of MVs, and the therapeutic application of MVs in VC.

Link: https://doi.org/10.3389/fcell.2022.825622

There is good evidence for particulate air pollution to accelerate degenerative aging. The proposed underlying mechanisms relate to inflammation, as particles can inflame lung tissue, thereby contributing to greater chronic inflammation throughout the body in later life. Separately, declining sense of smell correlates with aging as well, particularly with the incidence of neurodegenerative conditions, likely because similar underlying mechanisms contribute to both. Those mechanisms include the chronic inflammation of aging and its disruptive effects on cell and tissue function. Thereby it is perhaps not surprising to see researchers discover a correlation between olfactory decline and air pollution.

Among sensory dysfunctions, loss in the sense of smell, olfaction, is particularly pronounced in older age. Olfactory deficits are associated with a number of health conditions such as depressive symptoms and frailty, as well as shorter survival. An important fact is that olfactory impairment has exceptionally high prevalence rates among patients with neurodegenerative diseases and may constitute one of the first noncognitive manifestations of an impending dementia.

Given that the olfactory system is directly exposed to the outside environment, it has been speculated that part of the olfactory loss observed in older age may arise from cumulative damage of xenobiotics. For example, an increased exposure to air pollution may lead to olfactory loss, especially among middle-age or older adults for whom xenobiotic exposure has accumulated over a longer time. Sourcing mainly from traffic exhaust and other fuel-burning operations, the smallest particulates, with aerodynamic diameter of less than 2.5μm (PM2.5), are among the most harmful forms of air pollution for human health.

We hypothesized higher exposure to common airborne pollutants to be associated with a faster rate of decline in olfactory identification ability. We tested this hypothesis using a well-characterized population-based sample with spatially detailed data of long-term exposure to air pollution (PM2.5 or NOx) and repeated olfactory identification tests across 12 years of follow-up. Participants showed significant decline in odor identification ability for each year in the study (β=-0.20). After adjustment for all covariates, residents of third (β=-0.09) and fourth (β=-0.07) exposure quartiles of PM2.5 had faster rates of olfactory decline than residents from the first quartile.

Our results suggest an association between air pollution exposure and subsequent olfactory decline. We speculate that cumulative effects of airborne pollutants on the olfactory system may be one underlying cause of olfactory impairment in aging.

Link: https://doi.org/10.1289/EHP9563

As illustrated by today's research materials, the state of the art in spinal cord regeneration is improving. Scientists have produce engineered implants consisting of stem cells and hydrogel scaffold material intended to provide an environment conducive to nerve regeneration, and the results in mice are promising. Considered at the high level, this sort of work on implanted scaffolds containing a mix of cell types has been going on for two decades or more. The important advances are all in the details, building the right sort of environment of cells, cell signaling, and supporting metabolites.

All mammals are in principle capable of regenerating nerves. Those nerves were, after all, constructed during early life and then later maintained. Unfortunately adult mammalian tissues have suppressed much of the regeneration that can take place in a developing embryo or very young child. Researchers in the field of regenerative medicine are thus attempting to find the points of control and regulation that will bypass that suppression, allowing cells in injured nerve tissue to act as they did during development. The results here seem an important step in that direction.

Researchers successfully engineer world's first 3D human spinal cord tissue transplant

Researchers have engineered 3D human spinal cord tissues and implanted them in an animal model with long-term chronic paralysis, demonstrating high rates of success in restoring walking abilities. Now, the researchers are preparing for the next stage of the study, clinical trials in human patients. They hope that within a few years the engineered tissues will be implanted in paralyzed individuals enabling them to stand up and walk again.

"Our technology is based on taking a small biopsy of belly fat tissue from the patient. This tissue, like all tissues in our body, consists of cells together with an extracellular matrix comprising substances like collagens and sugars. After separating the cells from the extracellular matrix we used genetic engineering to reprogram the cells, reverting them to a state that resembles embryonic stem cells - namely cells capable of becoming any type of cell in the body."

The human spinal cord implants were then implanted in two different groups of animal models: those who had only recently been paralyzed (the acute model) and those who had been paralyzed for a long time (the chronic model) - equivalent to one year in human terms. Following the implantation, 100% of the animals with acute paralysis and 80% of those with chronic paralysis regained their ability to walk. Encouragingly, the model animals underwent a rapid rehabilitation process, at the end of which they could walk quite well.

Regenerating the Injured Spinal Cord at the Chronic Phase by Engineered iPSCs-Derived 3D Neuronal Networks

Cell therapy using induced pluripotent stem cell-derived neurons is considered a promising approach to regenerate the injured spinal cord (SC). However, the scar formed at the chronic phase is not a permissive microenvironment for cell or biomaterial engraftment or for tissue assembly. Engineering of a functional human neuronal network is now reported by mimicking the embryonic development of the SC in a 3D dynamic biomaterial-based microenvironment. Throughout the in vitro cultivation stage, the system's components have a synergistic effect, providing appropriate cues for SC neurogenesis. While the initial biomaterial supported efficient cell differentiation in 3D, the cells remodeled it to provide an inductive microenvironment for the assembly of functional SC implants. The engineered tissues are characterized for morphology and function, and their therapeutic potential is investigated, revealing improved structural and functional outcomes after acute and chronic SC injuries. Such technology is envisioned to be translated to the clinic to rewire human injured SC.

Mitochondria, the power plants of the cell, are the evolved descendants of ancient symbiotic bacteria. They have a small remnant mitochondrial genome, but over time most of the proteins necessary to mitochondrial function migrated to the nuclear genome. Such proteins are produced in the normal way in and around the cell nucleus, and are then imported into mitochondria for use. Researchers here investigate how this import system relates to longevity, finding that it can be adjusted in ways that influence quality control mechanisms and other aspects of mitochondrial metabolism.

Sustained mitochondrial fitness relies on coordinated biogenesis and clearance via mitophagy. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology.

We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response (UPRmt), orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

Link: https://doi.org/10.1038/s41467-022-28272-1

Maintaining physical fitness with advancing age has numerous benefits. This study is one of many to show that cognitive function is better in fitter older adults. Many distinct mechanisms are likely involved, from the usual suspects, such as improved autophagy throughout the body, a slowing of vascular aging, and improved blood flow to the brain, to indirect links mediated by the effects of exercise on the gut microbiome and its production of metabolites that can increase neurogenesis. Regardless, exercise costs little. Undertaking more of it is a good plan.

All 70- to 77-year-olds in Trondheim were invited to the Generation 100 study in 2012. Those who agreed to participate were randomly assigned to five years of exercise of various kinds. One group would primarily do high intensity intervals, a second group would mainly go for walks or do other exercise with moderate intensity, and the last group would try to follow the activity recommendations of the health authorities to be physically active for at least 150 minutes each week.

"Our results show that organized training follow-up may have given older men, but not older women, better cognitive function and lowered the probability of mild cognitive impairment. But all in all, it seems that the most important thing is that you actually train in a way that increases your fitness, regardless of whether you get organized help to be physically active or not."

In the groups that received follow-up with high-intensity training and training with moderate intensity, respectively, we found somewhat greater loss of brain volume in deep areas of the brain than among those who trained themselves. But we have to emphasize that everyone in the Generation 100 study - regardless of the form of exercise they did - had less brain loss than expected for people in their 70s. The group that trained on their own without organized follow-up had the least shrinkage in the hippocampus and thalamus.

The 70-77-year-old participants on average had the same cognitive abilities after five years as at start-up, and that during the study period they even improved on some of the tests. The results show that being in good shape like the Generation 100 participants were, is important for maintaining good brain function.

Link: https://norwegianscitechnews.com/2022/02/older-people-in-good-shape-have-fitter-brains/

In today's open access paper, researchers discuss immunization with Mycobacterium vaccae as an approach to reduce the inflammatory overactivity of the aged immune system. Researchers have made some initial inroads into studying the way in which this bacteria can alter the function of the immune system, and here the focus is on immune cells in the brain. A growing body of evidence points to microglia, innate immune cells of the central nervous system, as an important contributing cause of age-related neurodegeneration. These cells react to increased molecular damage, inflammatory signaling generated by senescent cells, and so forth, all of which is far more prevalent in the old brain than in the young brain. They become activated and inflammatory. The result is chronic inflammation in brain tissue and consequent disruption of cell and tissue function.

From a self-experimenter's perspective, Mycobacterium vaccae immunization is an interesting approach. Large clinical trials of Mycobacterium vaccae immunization have taken place for reasons unrelated to inflammation, and thus a good deal of safety data already exists. A quick look online suggests that it is practical to purchase Mycobacterium vaccae in a useful form, given a little work. The protocol used in rats in the paper here is as simple as a few weekly injections of a small amount of bacteria. While it is next to impossible to assess what is going on in the microglial population of the human brain, there are plenty of assays that might be used to assess the burden of systemic inflammation. That said, this is an initial observation that needs more research and reading to back it up; it may not be as interesting as it seems at first glance.

Mycobacterium vaccae immunization in rats ameliorates features of age-associated microglia activation in the amygdala and hippocampus

The lengthening of the human lifespan is associated with a rise in the burden of age-associated neurological disorders. Indeed, the aging process is characterized by a progressive shift from a homeostatic balance of inflammatory markers towards a "primed" or sensitized state. This increased neuroinflammatory priming makes the aged brain further susceptible to the disruptive effects of intrinsic and extrinsic factors like disease, infection, and stress, thereby elevating the risk of affective disorders, cognitive impairments, and neurodegenerative diseases in the aged population.

In addition to aging, chronic inflammatory conditions are increasing. Elevated chronic low-grade inflammation among modern urban societies may be caused by decreased microbial exposures - this is the foundation for the "Old Friends" hypothesis. Throughout evolution, the mammalian immune system developed tolerance to commensal environmental microbes. One such example is Mycobacterium vaccae (M. vaccae), a saprophytic bacterium found in soil, water, and mud that our ancestors frequently encountered. Reintroduction of these microbes in an excessively "clean" environment can suppress immune sensitization and reduce the risk for inflammatory diseases. M. vaccae has immunoregulatory properties, such as enhancing the induction of regulatory T cells and stimulating their production of anti-inflammatory cytokines, including interleukin (IL)-10 and transforming growth factor β. Peripheral immunization with M. vaccae also promotes an anti-inflammatory milieu in the central nervous system (CNS).

Elevated neuroinflammatory priming, as is observed due to aging, is mediated in part by microglia, the primary immunocompetent cell in the CNS. Microglia are dynamic cells that take on an array of phenotypes based on signals from their surrounding microenvironment. When microglia detect adverse signals or molecules, their morphology can drastically change.

Here, we investigate whether aging-related shifts in microglial morphology are ameliorated by immunization with anti-inflammatory M. vaccae. Morphological features of microglia evaluated in the amygdala, hippocampus, hypothalamus, and prefrontal cortex of adult (3 mos) and aged (24 mos) male rats. Our results demonstrate that aging leads to differential changes in microglia morphology and reactivity across brain regions, with the hippocampus being the most sensitive. Moreover, microglia in the amygdala and hippocampus appear most responsive to the anti-inflammatory effects of M. vaccae immunization, protecting against some age-associated microglia morphological changes.

The risk of suffering stroke, stratified by patient age and health status, has been well defined for decades. Look back at the Framington study data from the 1990s for example. The bottom line is that the odds average about 0.5%/year in your 50s through to 2.5%/year in your 80s, but whether or not you are in good shape matters a great deal when it comes to where you sit in relation to the average. Hypertension, raised blood pressure, is important in determining stroke risk for the obvious reasons: greater blood pressure means a greater chance of rupturing weakened blood vessels or atherosclerotic plaque. The reason why control of blood pressure can increase life expectancy is by reducing the risk of this and other forms of pressure damage throughout the body.

Data from the Framingham Study suggests that hypertension doubles the risk of stroke in older adults age 65-94, with a relative risk of 1.9 in men and 2.3 in women. While hypertension treatment has been shown to reduce stroke risk, it is less clear when stroke reduction occurs. In contrast, the harms of hypertension treatment, which include orthostatic hypotension, syncope, falls, and electrolyte abnormalities, appear to occur soon after treatment initiation. For example, the risk of falls and fractures was found to be increased in the first 7 to 45 days after the initiation of antihypertensive medications. Thus, while hypertension treatment decreases stroke risk over time, it can also lead to an increased risk for adverse effects.

To help clinicians identify, which patients are most likely to benefit from hypertension treatment (and which patients are more likely to be harmed), our objective was to determine the TTB of hypertension treatment for the primary prevention of stroke. We conducted a survival meta-analysis of major randomized clinical trials to determine the time to benefit (TTB) for various stroke absolute risk reduction (ARR) thresholds.

We determined that 200 adults aged ≥65 years would need to be treated for 1.7 years to avoid 1 stroke (ARR = 0.005). Since the overwhelming majority of older adults have a life expectancy of more than 1.7 years, these results suggest that almost all older adults with hypertension would benefit from treatment. We found substantial heterogeneity across studies suggesting that for older adults with poorly controlled hypertension, systolic blood pressure (SPB) higher than 190 mmHg, the TTB to prevent 1 stroke for 200 persons treated is likely substantially shorter than 1.7 years. Conversely, for older adults with relatively well-controlled hypertension (i.e., SBP less than 150 mmHg), the TTB to prevent 1 stroke for 200 persons treated is likely substantially longer than 1.7 years.

Link: https://doi.org/10.1111/jgs.17684

Researchers here look at simple, broad dietary changes and process existing data to see the expected effects on human life expectancy. They suggest that the difference between a poor diet and a good diet maintained across much of life is a decade of life expectancy, a surprisingly large number give that studies suggest that many common forms of aerobic exercise, such as jogging, appear to top out at an additional five years of life expectancy. When looking at high level data for diet, it is worth remembering that calorie intake is probably affected, and reduced calorie intake has a sizable effect on health. Another point to consider is how diet influences aging of the gut microbiome, and the presently unknown degree to which that is an important mediating factor in the effects of dietary composition on life span.

Based on meta-analyses and data from the Global Burden of Disease study, we used life table methodology to estimate how life expectancy (LE) changes with sustained changes in the intake of fruits, vegetables, whole grains, refined grains, nuts, legumes, fish, eggs, milk/dairy, red meat, processed meat, and sugar-sweetened beverages. We present estimates for an optimized diet and a feasibility approach diet. An optimal diet had substantially higher intake than a typical diet of whole grains, legumes, fish, fruits, vegetables, and included a handful of nuts, while reducing red and processed meats, sugar-sweetened beverages, and refined grains. A feasibility approach diet was a midpoint between an optimal and a typical Western diet.

A sustained change from a typical Western diet to the optimal diet from age 20 years would increase LE by more than a decade for women from the United States (10.7 years) and men (13.0 years). The largest gains would be made by eating more legumes (females: 2.2; males: 2.5), whole grains (females: 2.0; males: 2.3), and nuts (females: 1.7; males: 2.0), and less red meat (females: 1.6; males: 1.9) and processed meat (females: 1.6; males: 1.9). Changing from a typical diet to the optimized diet at age 60 years would increase LE by 8.0 years for women and 8.8 years for men, and 80-year-olds would gain 3.4 years. Change from typical to feasibility approach diet would increase LE by 6.2 years for 20-year-old women from the United States and 7.3 years for men.

In conclusion, a sustained dietary change may give substantial health gains for people of all ages both for optimized and feasible changes. Gains are predicted to be larger the earlier the dietary changes are initiated in life.

Link: https://doi.org/10.1371/journal.pmed.1003889

Today's open access paper provides a conservative view of present efforts to run clinical trials for interventions that target mechanisms of aging. This is a thin field so far: largely calorie restriction, calorie restriction mimetics such as mTOR inhibitors, compensation for mitochondrial decline in the form of NAD+ upregulation, and senolytics. The latter are the only option likely to produce eye-opening results, at least going by the animal data. Only a few senolytic trials are underway, however, and results are arriving only very slowly.

I would say that the authors here put too much weight on the possible problems that lie ahead. But they are right in that the outcomes have been largely unimpressive so far. The majority of trials have used unimpressive approaches, such as NAD+ upregulation via vitamin B3 derivatives. When the therapy reproduces only a small slice of the benefits of exercise, it perhaps isn't surprising to find that only marginal benefits result. When there are side-effects and problems, even minor ones, therapies that produce only marginal benefits tend to fail the cost-benefit consideration. We should in any case be aiming higher.

Clinical Trials Targeting Aging

Clearly, several trials have shown that targeting aging is feasible in humans. Calorie restriction has been associated with protective cardiovascular effects (lowered blood pressure and improved lipid profile), improved mitochondrial biogenesis, and metabolic efficiency (increased insulin sensitivity). A drawback of calorie restriction is that the feasibility is quite low for most humans. NAD+ supplements are safe in humans and increase NAD+-related metabolites but the influence on cellular energy-sensing pathways, and aging itself, has not shown clear results. Trials with senolytics have shown promising systemic results in subjects with idiopathic pulmonary fibrosis, diabetes, and kidney dysfunction. Nevertheless, senescence is an essential anti-cancer mechanism and interfering with this may be associated with cancer development. Further, mTOR inhibition causes improved mitochondrial function, dermatological skin improvements, and overall improved immune function in elderly individuals, possibly by lowering immunosenescence.

An important feature of potential aging drugs must be a relative absence of side-effects. Here, the benefit of utilizing wide-spread drugs that are approved for treatment of other diseases is that safety and tolerability is already thoroughly investigated, making it possible to commence larger-scale trials sooner. However, if treatment duration is prolonged periods of time, the health gaining effects must outweigh potential side-effects. For example: Dasatinib can cause gastrointestinal bleeding and liver damage. A possible approach to avoid this may be combining medication, i.e., handling rapamycin-caused glucose dysmetabolism with metformin

A bump on the road for expansion of aging trials is the inclusion of mainly healthy subjects in current anti-aging clinical trials, as long lists of wide-spread morbidities and medication often are among exclusion criteria. Thus, studies may include only exceptionally healthy elderly where effects of therapies targeting aging may be less efficient. Further, this could cause a blind-spot in catching potential side-effects of aging treatments as the side-effects may be related to other conditions. Instead, one could consider having slightly less stringent inclusion criteria which would allow individuals with mild chronic diseases (eg. hypertension) to be included. Similarly, an estimated 1/3 of all elderly receive five or more prescription drugs, potentially resulting in missed drug-drug interactions.

Medication often has a therapeutical concentration window, where too little poses no effect and too much is toxic. The same principle is relevant in anti-aging treatment but may include an additional temporal aspect. Initiation of some anti-aging treatments may require early intervention and might not be efficient if subjects are already old, while other treatment forms may show promising results in the elderly but cause unwanted, harmful side-effects in healthy, young subjects. This temporal therapeutical window has been experimentally observed in cancers and could cause major issues for anti-aging clinical trials. If no effect of a treatment is observed due to "incorrect" age of subjects or if it simply has no effect in any age-group can only be investigated by comparing identical studies on different age-groups.

In conclusion, clinical trials targeting aging in humans have shown promising but limited results on biomarkers so far.

Cognitive function depends on maintenance of the dynamic network of synaptic connections between neurons in the brain. In the study noted here, researchers assessed markers of synaptic density and function in postmortem human brains, and found a positive correlation with exercise regardless of the state of neurodegeneration. This is yet another good reason to maintain physical fitness into later life, keeping up with regular exercise. Supporting evidence suggests that a range of mechanisms link exercise with improved synaptic function, ranging from the fairly direct connection of reduced inflammation, and thereby improved performance in the cell populations that help to maintain synapses, to quite indirect connections involving the gut microbiome and generation of metabolites that change cell function in the brain.

The Memory and Aging Project (MAP), has been leading a longitudinal, prospective study since 1997 with volunteers who agree to undergo periodic cognitive and psychomotor assessments and to donate their organs for scientific purposes after death. The design of this study makes it possible to correlate daily habits and health states directly with structural and functional alterations in the brains of the participants.

The latest publication of that project presents results for 404 individuals whose physical activity was monitored with wristwatch or wristband-based devices for an average of 3.5 years ante-mortem. After death, samples were collected from up to twelve brain areas essential for cognitive and psychomotor skills; quantitative and functional analyses of eight synaptic proteins were performed on these samples, and a comprehensive histopathological evaluation, which examines ten neuropathologies associated with ageing, was made.

The results confirmed that higher rates of daily physical activity are associated across the board with an enrichment in the quantity and functionality of all the synaptic proteins analysed. This association was found to be most pronounced in brain regions related to motor control, such as the caudate nucleus and putamen. Furthermore, the relationship between physical exercise and synaptic density was independent of both the neuropathological load found in the same brain areas and the presence of pathologies affecting motor skills, indicating that physical activity can be beneficial for any elderly person regardless of their health status.

However, when analysed longitudinally, data indicated that the beneficial effects of physical exercise are highly volatile, as those participants with a high physical routine during early life and who discontinued this habit in the last two years of life had synaptic densities similar to those observed in more sedentary participants. In short, this study shows that physical exercise, even at an advanced age, contributes either towards promoting synaptogenesis processes or towards increasing synaptic resilience against the deleterious effects of neuropathological lesions."

Link: https://www.ehu.eus/en/web/campusa-magazine/-/physical-exercise-during-ageing-protects-brain-health

Mitochondrial DNA damage is thought to be important in aging, perhaps contributing broadly to general declines in mitochondrial function, perhaps leading to a small population of highly dysfunctional cells that export damaging oxidative molecules into surrounding tissues. The initial use for biotechnologies that can edit mitochondrial DNA is to fix inherited conditions, in which the mutational damage is the same in many mitochondria throughout the body. The challenge in adapting this approach to age-related mitochondrial DNA damage is that this damage is random, different in every cell it takes place in. It is likely, therefore, that approaches other than mitochondrial DNA editing will receive the most attention and funding when it comes to treating mitochondrial aging.

Our cells contain mitochondria, which provide the energy for our cells to function. Each of these mitochondria contains a tiny amount of mitochondrial DNA. Faults in our mitochondrial DNA can affect how well the mitochondria operate, leading to mitochondrial diseases, serious and often fatal conditions. There are typically around 1,000 copies of mitochondrial DNA in each cell, and the percentage of these that are damaged, or mutated, will determine whether a person will suffer from mitochondrial disease or not. Usually, more than 60% of the mitochondria in a cell need to be faulty for the disease to emerge, and the more defective mitochondria a person has, the more severe their disease will be. If the percentage of defective DNA could be reduced, the disease could potentially be treated.

Researchers recently used a biological tool known as a mitochondrial base editor to edit the mitochondrial DNA of live mice. The treatment is delivered into the bloodstream of the mouse using a modified virus, which is then taken up by its cells. The tool looks for a unique sequence of base pairs - combinations of the A, C, G and T molecules that make up DNA. It then changes the DNA base - in this case, changing a C to a T. This would, in principle, enable the tool to correct certain 'spelling mistakes' that cause the mitochondria to malfunction.

There are currently no suitable mouse models of mitochondrial DNA diseases, so the researchers used healthy mice to test the mitochondrial base editors. However, it shows that it is possible to edit mitochondrial DNA genes in a live animal. "This is the first time that anyone has been able to change DNA base pairs in mitochondria in a live animal. It shows that, in principle, we can go in and correct spelling mistakes in defective mitochondrial DNA, producing healthy mitochondria that allow the cells to function properly."

Link: https://www.cam.ac.uk/research/news/study-in-mice-shows-potential-for-gene-editing-to-tackle-mitochondrial-disorders

In a recent post, I suggested that is practical and useful for small organizations to run low-cost clinical trials in large numbers in order to build physician support for treatments for aging that should, by rights, already be in the clinic. The senolytic treatment of dasatinib and quercetin is the most obvious candidate, given its low cost, availability for off-label use, broad, large, and reliable benefits in animal models of aging and age-related disease, and human evidence for efficacy in clearing senescent cells to a similar degree as it does in mice.

Today I'll propose a different angle on early, small trials. In this case the goal is to fast-track access for human volunteers to whole-body partial reprogramming. In partial reprogramming, cells are exposed to Yamanaka factors for a limited time, long enough to reset epigenetic marks to a youthful configuration, but (hopefully!) not long enough for any significant number of cells to lose their differentiated state and become induced pluripotent stem cells capable of forming tumors. In mice, a variety of gene therapy approaches have been used to introduce expression of reprogramming factors, and in the short term the benefits appear interesting enough to follow.

As long-term readers might recall, I've long been dismissive of attempts to adjust epigenetic changes characteristic of aging, as (a) these changes were, in my eyes, a long way downstream from root causes, and (b) the research community was likely to try to make these changes one at a time, with limited individual benefit resulting from any given intervention. What changed my mind on this was the discovery that cycles of DNA damage and repair cause characteristic age-related epigenetic changes. That work needs expansion and replication, but it places some sizable fraction of epigenetic change very much closer to the root causes of aging than previously thought, and makes reversal of those changes a good point of intervention if there is a cost-effective way of doing it. Which there is, in principle, in the form of partial reprogramming.

A great deal of funding is now devoted to the matter of developing partial reprogramming into therapies. NewLimit will be much more nimble than the behemoth that Altos Labs has become, and Turn.bio nimbler still, but I'd still expect a decade to pass between where we are now and the first partial reprogramming therapies becoming available in the clinic in any meaningful sense. These entities will conduct a significant amount of preclinical research, and will be following the standard regulatory playbook thereafter. That takes a long time. Even then, there is a strong chance that the first therapies will be very cautious implementations, such as by being limited to the treatment of retinal diseases and only introduced into the eye.

As an alternative, I believe it would be feasible for a smaller, more agile, directed group to put together a gene therapy for most-of-the-body expression of reprogramming factors and administer it in a small trial of volunteers outside the US, accomplishing that goal in two years or so. The important challenges in reaching that milestone in just a few short years, likely consuming most of that time, are people matters rather than technical matters.

A good approach for a gene therapy capable of only short-term expression appropriate to partial reprogramming would be lipid nanoparticles (LNPs) carrying mRNA encoding the Yamanaka factors, to be injected intravenously in initially low and then ascending doses in human volunteers. The LNPs would be one of the later generation of low immunogenicity variants, while the mRNA would be optimized to reduce immunogenicity in the ways that are presently standard practice in the industry. These are existing technologies, a known sequence for expression of the reprogramming factors, and a matter of running a simple but multi-step manufacturing process that involves two distinct companies and some shipping back and forth.

This gene therapy really doesn't have to be produced using highly expensive, slow Good Manufacturing Practices (GMP) methods in order to be reasonably safe. While some medical technologies do require great care in their manufacture, in this case low-cost research grade materials will do just fine. To ensure correct manufacture at reasonable cost, one runs a quality control study for each batch in cell cultures and in mice, looking for expression of proteins, LNP size, correct sequence of mRNA, and a few other items. That data should be enough to convince anyone that the result is as expected. When injecting into humans, doses should start very low in order to assuage concerns about unexpected immunogenicity.

From a technical perspective, good options for manufacturing of the LNPs are Entos Pharmaceuticals and Acuitas Therapeutics, given what is known of the biodistribution (e.g. not passing the blood-brain barrier, so excluding brain tissue from reprogramming) and safety profiles of their products. For the mRNA there are more companies on the table, but TriLink Biotech is the leading manufacturer, owning some important process patents. The first people matter is to convince the LNP and mRNA companies to act as hands-off manufacturers for a group intending to perform human trials with research grade materials, likely outside the US. There will probably be reputational concerns amongst the leadership of companies that must work closely with the FDA.

All of the other people matters revolve around regulatory approval to perform these trials: which jurisdictions, how the regulatory bodies work in those regions, finding willing clinic owners, and so forth. The Bahamas is a favorable location for a number of groups that are presently setting up clinics for potential anti-aging therapies and would likely be interested in enabling a fast track to partial reprogramming trials. That said, given the good relationship between Bahamas regulators and the FDA I suspect they would require some form of GMP or GMP-like manufacture, significantly increasing costs.

Healthy volunteers in middle age would be a better choice at the outset of this project than those who are very old or very ill, as they will be more resilient in the case of, for example, unexpected immunogenicity. When looking for efficacy, outcomes to measure include epigenetic age, all the omics data that is shown to be rejuvenated by partial reprogramming in mice, and physical function: kidney and liver function, immune function, blood pressure, aerobic capacity, and so forth. The most important question is that of cancer risk, and regardless of how much is spent on clinical trials, or whether they are conducted by large or small organizations, that data will only emerge many years later.

Conducting this project seems to me largely an exercise in organization and finding the funding, with no major technical roadblocks. The big unknown, cancer risk, will remain a big unknown for a long time yet.

Researchers here report on an interesting work of comparative biology, looking for common metabolic factors in cells, tissues, and species that are capable of proficient regeneration such as regrowth of limbs and organs. Are there commonalities between the metabolism of deer antler regrowth and salamander limb regrowth, and can one follow those commonalities into the differences between stem cells and somatic cells? Perhaps. This work is a starting point, and it will be interesting to see where it leads.

From lower animals to humans, every species is endowed with a certain degree of regeneration. For example, axolotl, the Mexican salamander, is evolutionarily primitive vertebrate known to possess a higher regenerative capacity than mammals. Another example is the deer antler, which is the only organ capable of complete regeneration in mammals. In most mammals, the limited anatomical and functional recovery capabilities reside in young tissue and decline with age, leading to compromised tissue repair after injury. Compared to stem cells from regenerative tissues of the axolotl limb and the deer antler, human stem cells, such as human mesenchymal stem cells (hMSCs), possess a relatively limited capacity for regenerative repair of damages to vital tissues and organs, but gradually lose such capacity with age. Whether molecular characteristics between these naturally occurring regeneration processes are evolutionarily conserved across species is unknown.

Using comparative methods to describe the similarities and differences between species is a powerful strategy to discover the regulatory mechanisms that underline vital life events, such as regeneration. Here, we sought to understand how metabolic regulation intersects with inherent regenerative capacity using comparative approaches. Samples for this study included i) species that are more primitive on the evolutionary scale but can renew entire organs, and ii) higher species in evolution that have lost full organ regenerative capacity but retain a limited capacity for tissue repair. We systematically depicted metabolic profiles in various regeneration-related contexts, and we discovered that high pyrimidine and fatty acid metabolism was shared across species, tissues, and cells with high regenerative capacity. We identified uridine as a pro-regenerative metabolite that promoted human stem cell activity and enhanced regeneration in multiple tissues in mammals. These observations will open new avenues for metabolic intervention in tissue repair and regeneration.

Link: https://doi.org/10.1038/s41421-021-00361-3

One of the more interesting questions regarding Alzheimer's disease is why it only arises in some of the people with well-known risk factors. Only some people with higher levels of chronic inflammation. Only some frail people. Only some obese people. Only some people with detectable amyloid aggregation in the brain, as noted in the materials here. A plausible explanation, though still quite possibly not the right explanation, is that persistent viral infection is the driving force in Alzheimer's disease. Only a fraction of the population is significantly impacted in this way by varieties of herpesvirus, which seems a better fit than theories of disease progression involving mechanisms that operate in everyone.

Including nearly 20,000 participants, the largest study on amyloid prevalence to date estimates that a third of cognitively normal people older than 70 have amyloid building up in their brains. Compared amyloid prevalence across age, cognitive status, ApoE genotype, and by biomarker modality (i.e., CSF versus PET). A total of 10,139 participants in 50 cohorts had undergone amyloid-PET scans, while 8,958 participants across 51 cohorts had had CSF Aβ42 measured; only 1,571 underwent both.

Among those without dementia, amyloid cropped up in 24 percent of those with normal cognition, 27 percent of people with subjective cognitive decline, and 51 percent of people with mild cognitive impairment. Findings were similar whether amyloid-PET or CSF Aβ42 was used. Amyloid prevalence increased with age among those without dementia. For example, based on the adjusted CSF Aβ42 measurements, 17 percent of cognitively normal people between the ages of 50-54 had evidence of amyloid. By age 70, a third did, and by age 95, more than half did.

The size of this study gave the researchers enough statistical power to compare amyloid prevalence across different ApoE genotypes. E4/E4 carriers started accumulating amyloid at the youngest age, followed by E3/E4, E2/E4, E3/E3, and E2/E3 carriers. Notably, the amyloid prevalence among E3/E4 carriers was 10 percent higher than it was among E2/E4 carriers across all groups without dementia, highlighting a protective effect of the E2 allele.

Link: https://www.alzforum.org/news/research-news/amyloid-lurks-third-cognitively-normal-people-over-70

The thymus is responsible for turning thymocytes produced in the bone marrow into T cells of the adaptive immune system, in a complicated process of selection. This system is highly productive in youth, but active thymic tissue atrophies with age. This occurs for reasons that are far from fully explored, but may involve complex systemic issues related to rising inflammation and ongoing exposure to pathogens. As the thymus atrophies, the supply of T cells diminishes, and this loss of reinforcements is one of the major causes of immune aging. The T cell component becomes ever more full of exhausted, damaged, misconfigured, and senescent cells.

In this context, today's research materials are very interesting indeed. The authors report on their demonstration that a couple of years of mild calorie restriction in humans (a 14% reduction in calorie intake) can produce regrowth of the atrophied thymus. A very striking cross-sectional MRI image is provided in the publicity materials. The researchers go into some detail as to which of the countless metabolic changes produced in response to a reduced calorie intake are responsible for these effects. They point to PLA2G7 downregulation, which may be a target for future therapies to mimic this outcome. That PA2G7 downregulation suppresses inflammation is a point of support for inflammation-centric hypotheses of age-related thymic atrophy.

The study includes imaging and metrics for the thymus, but looks to be light on important details regarding the T cell output of the thymus and related immune system parameters. Unfortunately, this is par for the course in studies of thymus regrowth and resulting restoration of more youthful T cell production. Researchers either measure the size and structure of the thymus, or the relevant immune system parameters, and almost never both of these items in the same study.

Calorie restriction trial reveals key factors in extending human health

New research is based on results from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) clinical trial, the first controlled study of calorie restriction in healthy humans. For the trial, researchers first established baseline calorie intake among more than 200 study participants. The researchers then asked a share of those participants to reduce their calorie intake by 14% while the rest continued to eat as usual, and analyzed the long-term health effects of calorie restriction over the next two years.

The team started by analyzing the thymus, a gland that sits above the heart and produces T cells, a type of white blood cell and an essential part of the immune system. The thymus ages at a faster rate than other organs. By the time healthy adults reach the age of 40, 70% of the thymus is already fatty and nonfunctional. And as it ages, the thymus produces fewer T cells.

The research team used magnetic resonance imaging (MRI) to determine if there were functional differences between the thymus glands of those who were restricting calories and those who were not. They found that the thymus glands in participants with limited calorie intake had less fat and greater functional volume after two years of calorie restriction, meaning they were producing more T cells than they were at the start of the study. But participants who weren't restricting their calories had no change in functional volume.

The researchers then honed in on the gene for PLA2G7, was one of the genes significantly inhibited following calorie restriction. PLA2G7 is a protein produced by immune cells known as macrophages. This change in PLA2G7 gene expression observed in participants who were limiting their calorie intake suggested the protein might be linked to the effects of calorie restriction. To better understand if PLA2G7 caused some of the effects observed with calorie restriction, the researchers also tracked what happened when the protein was reduced in mice in a laboratory experiment.

Reducing PLA2G7 in mice yielded benefits that were similar to what we saw with calorie restriction in humans. Specifically, the thymus glands of these mice were functional for a longer time, the mice were protected from diet-induced weight gain, and they were protected from age-related inflammation. These effects occurred because PLA2G7 targets a specific mechanism of inflammation called the NLRP3 inflammasome. Lowering PLA2G7 protected aged mice from inflammation.

Caloric restriction in humans reveals immunometabolic regulators of health span

The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span.

Senescent cells accumulate with age, and their secretions provoke chronic inflammation and tissue dysfunction. With this in mind, researchers have shown that cellular senescence correlates with atrial fibrillation in older people. Here is a more recent demonstration of this relationship. I'm not aware of a study that shows senolytic therapy to remove senescent cells is a useful treatment for atrial fibrillation, but evaluation of this approach seems a good idea, both in aged animal models and in human patients.

Atrial fibrillation (AF) is the most frequent arrhythmia in clinical practice and is closely associated with increased cardiovascular morbidity and mortality. Accumulating evidence has shown that the incidence and prevalence of AF increase with age. Moreover, aging is an important risk factor for AF recurrence. At the cellular level, aging is characterized by cellular senescence, a state of irreversible cell cycle arrest and loss of specialized cellular functions. Senescent cells accumulate with age; as a result of genotoxic stress or various chronic diseases, they contribute to tissue aging and have been implicated in age-related tissue dysfunction because of the accumulation of damaged cells at sites of tissue injury and remodeling.

Recently, researchers have investigated the link between AF and cell senescence, showing that endothelial or fibroblast senescence may pave the way for adverse atrial remodeling in AF by promoting proinflammatory, prothrombotic, and profibrotic responses. We sought to understand senescence in AF and the extent to which it aggravates the AF process. Twenty-six AF patients undergoing open-heart surgery were included, and 12 patients with sinus rhythm served as controls. Another cohort included 120 consecutive persistent AF patients with valvular heart diseases.

Compared with sinus rhythm, left atrial appendages (LAAs) with AF presented a significantly increased positive area of cellular senescence, with upregulated expression of p16, p21, and p53. Next, p21 mRNA was increased in patients with AF recurrence compared with that in patients without recurrence. Further, p21 was a significant independent predictor of AF early recurrence (odds ratio 2.97). This finding may help facilitate the search for new therapeutic approaches for antiaging therapy for AF.

Link: https://doi.org/10.14336/AD.2021.0619

A growing longevity industry is picking up ongoing academic projects in increasing numbers and working towards the clinical availability of therapies to treat aging. Amidst all the light and noise, one of the researchers in the field here asks for us not to overlook the need for more fundamental research. I agree, though I'd say that the most important portion of research not to be overlooked are the projects in the SENS rejuvenation biotechnology portfolio yet to make it to enthusiastic commercial development. To my eyes, the fastest way to find out more about how aging works is to implement and test specific rejuvenation strategies, each of which addresses only a narrow aspect of aging.

João Pedro de Magalhães has dedicated his career to understanding the biological puzzle of aging. With so much focus now being placed on developing new interventions in the longevity field, de Magalhães is concerned that the fundamental research into understanding why we age may be taking more of a back seat. "What you see in the field as a whole is that it's on an upwards trajectory, which makes it very exciting. I remember the first conference I went to in the field of aging, which must have been 20 years ago when I was a PhD student and there were only a couple of companies starting to work on aging. So it's impressive how much the field has grown in the past 20 years - it's really remarkable. Which is really about more and more people recognising aging as something that can be intervened in."

"I think on one hand that this is very exciting. But on the other hand, I also think it shows there has been a shift in the field away from studying mechanisms of aging. I'm not saying everybody's doing this, but, as a field, it's almost like we're giving up on trying to understand why we age and instead focus on the fact that we can manipulate aging in model systems and identifying interventions and therapies and drugs. I'm sure that we're going to develop therapies that work and it will be fantastic, from a health perspective, from a financial perspective and so on. But I also think most of what we're discovering, at the basic science level at the preclinical level is not going to work in humans. So I believe we still have to go after the difficult questions and the difficult problems, such as why we age. Let's go after the high-hanging fruit!"

Illustrating his concern in this area, de Magalhães points to a paper he co-authored with David Gems last year, which criticises the hallmarks of aging. "It's one of the articles I'm most proud of, because, although it may not make everybody happy, it's highlighting this issue, which is, in my view, the hallmarks are an oversimplification. In reality, there's still a lot of work to do to understand the process of aging, which is still very poorly understood. Even though it's not a low hanging fruit, even though it's difficult, we still need to have a better understanding of the mechanistic causes of aging, which, in my view, the hallmarks of aging does not provide."

Link: https://www.longevity.technology/why-we-age-are-we-losing-focus-on-longevitys-key-question/

Autophagy is the name given to a collection of cellular maintenance processes that identify and break down worn and unwanted proteins and structures in the cell. More efficient autophagy in principle produces better cell and tissue function, and, over the long term, slower aging. A sizable portion of the research community is interested in autophagy in the context of aging, but outside the development of calorie restriction mimetic drugs, few groups are working towards therapies intended to upregulate autophagy in a targeted fashion. A program in the Life Biosciences portfolio is one of the limited number of examples.

The ability of calorie restriction to lengthen healthy life in short-lived species is largely the reason that autophagy became interesting, though many approaches that slow aging in animal studies are characterized by upregulation of autophagy. In the case of calorie restriction, extension of life span depends on the correct operation of autophagy. A good number of studies provide other evidence that points to improved autophagy as the primary cause of health and longevity benefits resulting from a reduced calorie intake.

One of the many benefits produced by calorie restriction, and calorie restriction mimetics capable of upregulating autophagy, is a slowed decline of the immune system in later life. With this in mind, today's open access paper discusses the relationship between autophagy and immune aging. As in other considerations of autophagy, it is plausible that the more important portion of autophagic activity is the removal of worn and damaged mitochondria, the selective autophagy known as mitophagy. Mitochondria decline in effectiveness with age, in large part due to faltering mitophagy. This has detrimental effects throughout the body that include altered behaviors and capabilities of immune cells.

Autophagy takes it all - autophagy inducers target immune aging

Recently, a plethora of studies revealed that selective autophagy, in close association with immunometabolism, is key in modulating immunity and immune cell dynamics. In addition, autophagy is further involved in differentiation and proliferation of immune cells, although what exactly underlies molecular mechanisms remains partly elusive. Mounting evidence indicates that mitophagy, which encompasses selective degradation of damaged or excessive mitochondria, is an especially crucial regulator of innate immune cell function. Autophagy also prevents mitochondrial DNA escaping into the cytoplasm by maintaining mitochondrial homeostasis, which inhibits initiation of type I interferon signalling and, ultimately, inflammation. Furthermore, autophagy is essential for T cell immunity and its decline with age leads to immunosenescence.

During the last two decades, several trailblazing studies have suggested that innate and adaptive immunity are key to fight not only infectious diseases but also non-communicable diseases including typical age-related conditions, such as cancer. Considering that autophagy facilitates adaptive immune cell activation and differentiation, and partially reverses systemic immunosenescence via modulating T cell immunity, clinical implementation of autophagy inducers provides high therapeutic potential.

Drug discovery has identified numerous small compounds that can reverse age-associated effects via autophagy. These have been suggested to extend median and maximal lifespan, underpinned by in vivo and in vitro data obtained in various animal models. Importantly, lifestyle and nutrition, particularly exercise and dietary restriction enhance the autophagy pathway. Several repurposed and already FDA-approved drugs that either inhibit mTORC1 or activate AMPK have recently gained considerable attention as promising immunoprotective interventions that could be translated into clinic within the next decade. Here, we focus on the three most-promising drugs (rapamycin, metformin, and spermadine) and on dietary restriction as a lifestyle change.

The evidence from this study points to a tight coupling between age-related losses in different areas of cognitive function. This is more or less what one might expect to occur in a complex system that is undergoing chemical and small-scale structural damage. Such damage will tend to affect all emergent properties of the system. The goal of medical research and development should be to find ways to repair that damage and restore function, not attempt to otherwise compensate for ongoing losses.

At the age of 20, people usually find it easier to learn something new than at the age of 70. People aged 70, however, typically know more about the world than those aged 20. In lifespan psychology this is known as the difference between "fluid" and "crystallized" cognitive abilities. Fluid abilities primarily capture individual differences in brain integrity at the time of measurement, whereas crystallized abilities primarily capture individual differences in accumulated knowledge.

Accordingly, fluid and crystallized abilities differ in their average age trajectories. Fluid abilities like memory already start to decline in middle adulthood. In contrast. crystallized abilities such as vocabulary show increases until later adulthood and only evince decline in advanced old age. This divergence in the average trajectories of fluid and crystallized abilities has led to the assumption that people can compensate for fluid losses with crystallized gains. A study now shows that this compensation hypothesis has more limits than previously claimed.

The correlations between the two types of changes observed were very high. Thus, individual differences in cognitive development are, to a large extent, domain-general and do not follow the fluid-crystallized divide. What this means is that individuals who show greater losses in fluid abilities simultaneously show smaller gains in crystallized abilities, and persons whose fluid abilities hardly decline show large gains in crystallized abilities. These findings are in accordance with the everyday observation that some people remain mentally fit in many areas into very old age while others' cognitive functioning declines across the board. People whose memory is declining, also show a low gain in knowledge, even though they are in most need of such gains. Conversely, individuals with small fluid losses and strong crystallized gains are less likely to be in need of relying on compensatory processes to begin with.

Link: https://www.eurekalert.org/news-releases/942264

Much of what we'd like to know about cancer therapies takes a long time to emerge. Only now is the long term data available for the first CAR-T immunotherapies aimed at forms of leukemia in which cancerous cells are clearly and distinctly marked by characteristic surface features. The field has long since expanded, and researchers are at present trying to adjust CAR-T in order to apply this form of treatment to solid cancers. Long term remission is not the same as a cure, as cancer is a disease in which it remains challenging to say whether or not a few remnant cancer cells await a return at some future time. If one can make it ten years in remission, with no sign of cancer, however, that may well be a cure under the hood, the cancer gone and never to return.

The year was 2010, and Olson was one of the first people with chronic lymphocytic leukaemia to receive the treatment, called CAR-T cell therapy. When his doctors wrote the protocol for the clinical trial that Olson was involved in, they hoped that the genetically engineered cells might survive for a month in his body. They knew that cancer research could be heartbreaking; they didn't dare to expect a cure. But more than ten years later, the immune cells continue to patrol Olson's blood and he remains in remission. Doctors finally ready to admit what Olson suspected all along. "We can now conclude that CAR T cells can actually cure patients with leukaemia."

CAR-T cell therapies involve removing immune cells called T cells from a person with cancer, and genetically altering them so that they produce proteins - called chimeric antigen receptors, or CARs - that recognize cancer cells. The cells are then reinfused into the person, in the hope that they will seek out and destroy tumours. In the years since Olson's treatment, five CAR-T cell therapies have been approved by the US Food and Drug Administration, to treat leukaemias, lymphomas, and myelomas. It is estimated that tens of thousands of people have received CAR-T cell treatment.

But the therapy is expensive, risky and technically demanding. It remains a last resort, to be used when all other treatments have failed. Despite the treatment's success for Olson, not everyone experiences durable remission of their cancer. In the beginning, only about 25-35% of CAR-T cell recipients with chronic lymphocytic leukaemia experienced a complete remission of their cancer. With refinement, that percentage has increased over the years, he says, but some of these initial successes still lead to relapse. Tracking the treatment long-term could reveal clues as to what factors are important for lasting CAR-T cell success.

Link: https://www.nature.com/articles/d41586-022-00241-0

Naked mole rats exhibit negligible senescence, meaning that that individuals show a minimal functional decline as a result of aging until very late life. They exhibit a very low incidence of cancer. They are one of the most studied species in the context of the comparative biology of aging, the search for longevity assurance mechanisms in unusually long-lived species that might become the basis for therapies to treat aging in humans. That naked mole rats are mammals gives the hope that any discoveries are more likely to be relevant to our species than is the case for investigations of lower animals, such as the work on exceptional regeneration in salamanders or zebrafish.

In today's open access paper, the authors discuss heart function in aging naked mole rats. There is little speculation on mechanisms; the researchers involved only measured heart function. As is the case for most biological systems in the naked mole rat, an old heart performs about as well as a young heart. We know from other research that the harmful accumulation of senescent cells with age contributes to cardiac fibrosis and hypertrophy in mammals, while senescent cell behavior is unusually innocuous in naked mole rats. Other relevant issues that are less well investigated in the naked mole rat include calcification of cardiac tissue (where senescent cells also play a role, it seems) and stiffening of arteries due to cross-linking and other causes. It remains to be seen as to what can be learned from all of this.

Naked mole-rats maintain cardiac function and body composition well into their fourth decade of life

The prevalence of cardiovascular disease increases exponentially with age, highlighting the contribution of aging mechanisms to cardiac diseases. Although model organisms which share human disease pathologies can elucidate mechanisms driving disease, they do not provide us with innate examples how cardiac aging might be slowed or attenuated. The identification of animal models that preserve cardiac function throughout most of life offers an alternative approach to study mechanisms which might slow cardiac aging. One such species may be the naked mole-rat (NMR), a mouse-sized (40 g) rodent with extraordinary longevity (more than 37 years), and constant mortality hazard over its four decades of life.

We used a cross-sectional study design to measure a range of physiological parameters in NMRs between 2 and 34 years of age and compared these findings with those of mice aged between 3 months and 2.5 years. We observed a rapid decline in body fat content and bone mineral density in old mice, but no changes in NMRs. Similarly, rhythm disorders (premature atrial and ventricular complexes) occurred in aged mice but not in NMRs. Magnetic resonance and ultrasound imaging showed age-dependent increases in cardiac hypertrophy and diastolic dysfunction in mice which were absent in NMRs. Finally, cardiac stress tests showed an age-dependent decline in normalized cardiac output in mice, which was absent in NMRs.

This study demonstrates that unlike mice that exhibit pronounced declines in body composition and cardiac function commencing shortly after sexual maturity, NMRs can maintain tissue homeostasis throughout their four-decade long maximum lifespan. Furthermore, NMRs do not show any signs of diastolic dysfunction or cardiac hypertrophy and maintain similar functional cardiac reserve capacity at advanced age to that exhibited when young adults, at the prime of life. Collectively, these data reveal that the naked mole-rat provides a proof-of-concept that age-related declines in body composition and cardiac function are not inevitable. Elucidating these mechanisms may lead to the discovery of therapies to reduce the burden of age-associated cardiovascular pathology, morbidity, and mortality and thereby enhance quality of life in older humans.

25-hydroxycholesterol is an oxidized form of cholesterol, and researchers here demonstrate that it is senolytic to some degree in mice. This may be competitive with existing first generation senolytics; from the paper, it looks like it clears about half of the excess of senescent cells present in old mice, in muscle tissue at least. Like all other senolytics, its effectiveness likely varies widely by tissue type and location in the body. Oxidized cholesterols are largely thought to be harmful in the body, particularly because they can cause macrophages to become dysfunctional and accelerate the progression of atherosclerosis. It is unclear as to whether that could prove to be a blocking issue at the sort of doses and schedules used in senolytic therapy.

Researchers have shown that the endogenous metabolite 25-hydroxycholesterol (25HC) significantly reduced the burden of senescent cells in multiple cell types in both mice and human cell culture, and in live mice, where it showed particular efficacy in skeletal muscle. "Given that 25HC shares no common molecular motifs with other senolytics, it appears that this molecule represents a brand new class of potential interventions."

25HC is a little understood oxidized lipid involved in cholesterol metabolism. The team identified it after discovering that the molecule disrupted cellular senescence in CRYAB, a small heat shock protein which was upregulated upon senescence in nine different cell types from two species, mice and humans. Diseases associated with CRYAB include myopathies, diseases that affect muscles that control voluntary movement in the body.

Working in mouse and human cell cultures researchers isolated specific cell types from skeletal muscle, made them senescent and showed that 25HC could kill them selectively. The team then went on to test 25HC in aged mice; experiments showed 25HC improved their muscle mass. Researchers also determined that 25HC killed senescent cells in mouse dermal fibroblasts, and in primary human cells from the lung, heart, liver, kidney, and articular cartilage. "We are intending to use this molecule in multiple paradigms of aging and we're hoping that other researchers will start testing it as well."

Link: https://www.buckinstitute.org/news/a-naturally-occurring-metabolite-is-a-potent-senolytic-in-both-mice-and-human-cell-culture/

A growing number of rodent studies have demonstrated the ability of senolytics to improve cognitive function in old animals by clearing a sizable fraction of lingering senescent cells from aged tissues throughout the body. Specifically this means the dasatinib and quercetin combination, as both can cross the blood-brain barrier after oral administration. Researchers have undertaken a study in Alzheimer's patients, but it will be quite some time before results are published. Senescent cells generate inflammatory signaling, and inflammation in brain tissue is strongly implicated in the progression of neurodegenerative conditions. The degree to which this is the result of the activity of senescent cells in the brain versus the signaling of the many more senescent cells outside the brain is up for debate. Clearing such cells globally is in any case clearly beneficial in rodents.

Aging is associated with cognitive decline and accumulation of senescent cells in various tissues and organs. Senolytic agents such as dasatinib and quercetin (D+Q) in combination have been shown to target senescent cells and ameliorate symptoms of aging-related disorders in mouse models. However, the mechanisms by which senolytics improve cognitive impairments have not been fully elucidated particularly in species other than mice.

To study the effect of senolytics on aging-related multifactorial cognitive dysfunctions we tested the spatial memory of male Wistar rats in an active allothetic place avoidance task. Here we report that 8 weeks treatment with D+Q alleviated learning deficits and memory impairment observed in aged animals. Furthermore, treatment with D+Q resulted in a reduction of the peripheral inflammation measured by the levels of serum inflammatory mediators (including members of senescent cell secretome) in aged rats.

Significant improvements in cognitive abilities observed in aged rats upon treatment with D+Q were associated with changes in the dendritic spine morphology of the apical dendritic tree from the hippocampal CA1 neurons and changes in the level of histone H3 trimethylation at lysine 9 and 27 in the hippocampus. The beneficial effects of D+Q on learning and memory in aged rats were long-lasting and persisted at least 5 weeks after the cessation of the drugs administration.

Link: https://doi.org/10.18632/aging.203835

The gut microbiome changes with age, a collection of microbial species that live in symbiosis with their host, helping to process food. Beneficial species that generate metabolites needed by tissues decline in number, while harmful inflammatory populations grow in number. There is a bidirectional relationship between the aging of the immune system and the aging of the gut microbiome. The immune system is responsible for removing problem microbes, and when it falters in this task, the microbiome becomes more harmful to the host. In turn, problem microbes can trigger chronic inflammation, degrading immune function and tissue function. There are other issues involved in aging that negatively impact the relationship between body and microbiome, such as the declining integrity of the intestinal barrier, but immune system function is an important one.

The balance of populations in the human gut microbiome exhibits significant changes as early as mid-30s. A number of potential approaches exist to reverse these changes, some more proven and practicable than others. Fecal microbiota transplantation and flagellin immunization are probably the best of the options on the table: they are comparatively easily accomplished; there is supporting animal data; and these interventions are already tested to some degree in humans. In principle the right combination and amounts of probiotics should work, but I'm not aware of any great progress towards determining what those combinations and amounts should be, or even whether the necessary probiotics are presently manufactured at all. There is also little animal data to indicate anything more than modest benefits from present commonly used probiotics.

The small bowel microbiome changes significantly with age and aspects of the ageing process

The human gut microbiome, comprising bacteria, archaea, fungi, parasites, and viruses, has numerous, significant impacts on the physiology of the human host throughout its lifespan, including roles in nutrient absorption and metabolism, immune function, and even brain function and behavior. Following rapid colonization at birth, the gut microbiome undergoes dynamic changes during early childhood before settling into a relatively stable pattern that was thought to persist throughout adulthood, unless impacted by significant changes in diet, medications, or disease. However, recent studies have demonstrated that the gut microbiome changes with increasing age and that the diversity of the gut microbiome may influence longevity and healthy ageing.

A caveat is that these, like the majority of gut microbiome studies, relied on stool samples. Although stool is easier to procure and analyze, the small intestine is central to metabolism and the maintenance of homeostasis, and its microbial populations are significantly different from those in stool. Therefore, to explore the effects of ageing specifically on the small intestinal microbiome, we procured a total of 251 duodenal aspirates from subjects aged 18 to 80 years which had been collected as part of the REIMAGINE (Revealing the Entire Intestinal Microbiota and its Associations with the Genetic, Immunologic, and Neuroendocrine Ecosystem) study.

we demonstrate significant differences in the small intestinal microbiome in older subjects, using duodenal aspirates from 251 subjects aged 18-80 years. Differences included significantly decreased microbial diversity in older subjects, driven by increased relative abundance of phylum Proteobacteria, particularly family Enterobacteriaceae and coliform genera Escherichia and Klebsiella. Moreover, while this decreased diversity was associated with the 'ageing process' (comprising chronologic age, number of medications, and number of concomitant diseases), changes in certain taxa were found to be associated with number of medications alone (Klebsiella), number of diseases alone (Clostridium, Bilophila), or chronologic age alone (Escherichia, Lactobacillus, Enterococcus). Lastly, many taxa associated with increasing chronologic age were anaerobes.

In conclusion, this first examination of the effects of age and the ageing process on the small intestinal microbiome demonstrates that the duodenal microbiome changes with increasing age, with significant decreases in duodenal microbial diversity due to increased prevalence of phylum Proteobacteria, particularly coliforms and anaerobic taxa. Given the key roles of small intestinal microbes in nutrient absorption and host metabolism, these changes may be clinically relevant for human health during the ageing process.

It is quite rare for researchers to attempt combined treatments, unfortunately. The panoply of calorie restriction mimetics and other approaches to gently upregulate stress responses are individually not all that impressive, and it remains unclear as to which of them can be stacked for greater effect. In the treatment of aging, even the better approaches that produce actual and rapid rejuvenation, such as senolytic therapies to destroy senescent cells, will have to be stacked with one another. There are many different contributing causes of aging. Here, researchers report that a combination therapy carried out for a few months in aged mice produces improvements of 20-40% in physical function. That duration corresponds, very roughly, to a decade or more of sustained treatment in old humans.

Loss of physical performance, as seen in humans by decreased grip strength and overall physical fitness, is generally accepted to be a consequence of aging. Treatments to delay or reduce these changes or increase resilience to them are generally not available. In this preliminary study, 20-month-old male and female C57BL/6 mice were given either a standard mouse diet or a formulated mouse diet containing rapamycin (14 ppm), acarbose (1000 ppm), and phenylbutyrate (1000 ppm), or a diet containing one half dose of each drug, for 3 months. At the end of the study, performance on a rotarod and grip strength test was compared.

Rapamycin blocks mTOR, a protein shown to integrate signals from growth factors and nutrients to control protein synthesis. The anti-aging effect of downregulating mTOR was confirmed by the NIA Intervention Testing Program showing that rapamycin extended lifespan in mice. Arcabose is a popular type 2 diabetes medication used for glucoregulatory control, and it also increases mouse lifespan. Phenylbutyrate is clinically approved as an ammonia scavenger for urea cycle disorders in children, and is also an inhibitor of histone deacetylase. In aging mice, it enhances physical and cognitive performance.

In general, mice fed the full dose drug cocktail diet performed better on these assays, with significant improvements in rotarod performance in females fed the full dose cocktail and in grip strength in males fed the full dose cocktail, and females fed the low dose cocktail. These observations provide support for the concept that short term treatment with a cocktail of drugs that targets multiple aging pathways can increase resilience to aging, and suggests that this prototype cocktail could be part of a clinical therapeutic strategy for delaying age-related loss of physical performance in people.

Link: https://doi.org/10.31491/APT.2021.03.051

Researchers here discuss the rising expression of aquaporin-4 in the vasculature of the aging brain, particularly the choroid plexus, where cerebrospinal fluid is produced. That production decreases with age. Aquaporin-4 is one of a family of proteins that facilitates transfer of water through cell membranes, and it is an important part of the regulation of fluid in the brain. It is unclear as to whether this rising expression is (a) harmful, one of many detrimental alterations that take place in the aging vasculature and brain structures, and a contributing cause of reduced cerebrospinal fluid production, or (b) an ultimately unsuccessful attempt to compensate for some of those harms by increasing cerebrospinal fluid production.

The choroid plexus (CP) consists of specialized ependymal cells and underlying blood vessels and stroma producing the bulk of the cerebrospinal fluid (CSF). CP epithelial cells (CPCs) are considered the site of the internal blood-cerebrospinal fluid barrier, show epithelial characteristics (basal lamina, tight junctions), and express aquaporin-1 (AQP1) apically. In this study, we analyzed the expression of aquaporins in the human CP. As previously reported, AQP1 was expressed apically in CPCs. Surprisingly, and previously unknown, many cells in the CP epithelium were also positive for aquaporin-4 (AQP4), normally restricted to ventricle-lining ependymal cells and astrocytes in the brain.

Expression of AQP1 and AQP4 was found in the CP of all eight body donors investigated (age 74-91). We hypothesized that AQP4 expression in the CP was caused by age-related changes. To address this, we investigated mouse brains from young (2 months), adult (12 months) and old (30 months) mice. We found a significant increase of AQP4 mRNA in old mice compared to young and adult animals.

In the context of the morphological and functional changes associated with age and disease in the CP, the detection of AQP4 in CPCs and can be interpreted in two alternative scenarios. First, AQP4 expression could serve as a compensatory mechanism in old age to maintain CSF production known to be decreased. An alternative hypothesis can be inferred from AQP4 expression in the ependyma adjacent to the plexus epithelium. Here, AQP4 is expressed in the basolateral membrane domain of ependymal cells. Therefore, CPCs might differentiate over time into AQP4-positive cells, and the expression of AQP4 leads to an inverted transcellular water flow resulting in a reduced CSF production.

Link: https://doi.org/10.1007/s00018-022-04136-1

Every age-related disease that can be linked to the chronic inflammation of aging is likely driven in part by the accumulation of senescent cells. This is not only a matter of senescent cells present in the organs affected by disease, but also involves the burden of cellular senescence throughout the body. When lingering in significant numbers, senescent cells cause harm via their inflammatory secretions, the senescence-associated secretory phenotype (SASP). Secreted inflammatory signals can travel widely through the body, rousing the immune system to overactivity, and changing cell behavior for the worse.

Sarcopenia is the characteristic loss of muscle mass and strength that takes place with age. Linking sarcopenia to chronic inflammation, and indeed to senescent cells, is a new idea in the sense that the modern focus on cellular senescence in aging only began in earnest a decade ago or so (after another prior decade of a few voices trying to get more researchers to take it seriously). With the development of senolytic therapies to selectively destroy senescent cells in full swing for a few years now, scientists have been writing papers on the plausible role of cellular senescence in sarcopenia. Today's open access materials are an example of the type.

Cellular Senescence in Sarcopenia: Possible Mechanisms and Therapeutic Potential

Aging promotes most degenerative pathologies in mammals, which are characterized by progressive decline of function at molecular, cellular, tissue, and organismal levels and account for a host of health care expenditures in both developing and developed nations. Sarcopenia is a prominent age-related disorder in musculoskeletal system. Defined as gradual and generalized chronic skeletal muscle disorder, sarcopenia involves accelerated loss of muscle mass, strength, and function, which is associated with increased adverse functional outcomes and evolutionally refers to muscle wasting accompanied by other geriatric syndromes.

More efforts have been made to clarify mechanisms underlying sarcopenia and new findings suggest that it may be feasible to delay age-related sarcopenia by modulating fundamental mechanisms such as cellular senescence. Cellular senescence refers to the essentially irreversible growth arrest mainly regulated by p53/p21CIP1 and p16INK4a/pRB pathways as organism ages, possibly detrimentally contributing to sarcopenia via muscle stem cells (MuSCs) dysfunction and the senescence-associated secretory phenotype (SASP). Cellular senescence may have beneficial functions in counteracting cancer progression, tissue regeneration, and wound healing.

By now diverse studies in mice and humans have established that targeting cellular senescence is a powerful strategy to alleviating sarcopenia. However, the mechanisms through which senescent cells contribute to sarcopenia progression need to be further researched. We review the possible mechanisms involved in muscle stem cells (MuSCs) dysfunction and the SASP resulting from cellular senescence, their associations with sarcopenia, current emerging therapeutic opportunities based on targeting cellular senescence relevant to sarcopenia, and potential paths to developing clinical interventions genetically or pharmacologically.

Researchers here show that activated protein C (APC) is involved in the mechanisms that cause cell death and dysfunction subsequent to ischemia, the temporary loss of flow of blood to tissue, and reperfusion, the return of that supply. Much of the harm following a heart attack or stroke might be avoided if cells just behaved differently. Researchers found that APC activity is reduced in old tissues, and this makes cells more vulnerable. Upregulation of APC may help to somewhat reduce the consequences of ischemia.

APC, a protein circulating in blood, has both anticoagulant (blood clot prevention) and anti-inflammatory functions that can help protect cells from disease and injury. Endothelial protein C receptor (EPCR) - located both on cells lining blood vessels and on the surface of cell membranes, including heart muscle cells - is associated with increased APC production and regulates APC's subsequent cell signaling (or cell communication).

The stress of ischemia and reperfusion injury induced "shedding" of EPCRs in young and old wild-type mice - that is, a greater number of these receptors were cut from the heart muscle cell membrane and then moved into the bloodstream. This EPCR shortage (deficiency) in the heart can impair activated protein C signaling critical for favorably regulating energy metabolism and anti-inflammatory responses, preventing cell death, and stimulating other activities needed to protect cardiac muscle cells. While the hearts of the old and young wild-type mice both showed EPCR shedding, older hearts experienced a more severe EPCR deficiency and decline in APC signaling activity in response to reperfusion injury.

Administering APC or its derivatives helped reduce heart damage inflicted by ischemia and reperfusion, particularly in the old mice. Digging deeper, the researchers discovered that by stabilizing (maintaining) EPCR on the cardiac cell membrane, APC strengthens the aging heart's resistance both to heart attack-related ischemia and to injury associated with restoring coronary artery blood flow.

The researchers detailed how APC treatments improve cardiac function by regulating both acute (short-term) and chronic (longer-term) metabolic pathways. They demonstrated that enzyme AMPK (AMP-activated protein kinase) mediates an acute adaptive response to cardiac stress immediately following heart attack, while enzyme AKT (protein kinase B) regulates chronic metabolic adjustments to reperfusion stress over time. APC treatment led to better enzyme activity and more efficient energy balance needed to contract cardiac muscle cells and pump blood from the heart to the rest of the body.

Link: https://hscweb3.hsc.usf.edu/blog/2022/01/27/activated-protein-c-can-protect-against-age-related-cardiac-ischemia-and-reperfusion-injury-preclinical-study-finds/

In recent years, researchers have identified a variant of the gene BPIFB4 that correlates with longevity in humans, and in mice appears to suppress mechanisms in immune cells that contribute to chronic inflammation. In this paper, researchers use gene therapy to deliver the longevity-associated variant of BPIFB4 to old mice, and find that it reduces the presence of inflammatory immune cells showing markers of cellular senescence. The chronic inflammation of aging is known to contribute to many different age-related conditions, and the growing presence of senescent cells provides a sizable fraction of that inflammatory signaling. It is an important goal to find ways to suppress it without interfering in the necessary short-term inflammation needed to respond to infection and injury.

As we age, our body experiences chronic, systemic inflammation contributing to the morbidity and mortality of the elderly. The senescent immune system has been described to have a causal role in driving systemic aging and therefore may represent a key therapeutic target to prevent pathological consequences associated with aging and extend a healthy lifespan. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models halted the progression of cardiovascular diseases (CVDs) and frailty by counterbalancing chronic inflammation.

In the present study, we aimed to delineate the action of systemic adeno-associated viral vector-mediated LAV-BPIFB4 gene transfer (AAV-LAV-BPIFB4) on the deleterious age-related changes of the immune system and thereby the senescence-associated events occurring in C57BL/6J mice aged 26 months. Our in vivo data showed that 26-months-old mice had a higher frequency of CD45+SA-beta Gal+ immune cells in peripheral blood than young (4-months-old) C57BL/6J mice. Notably, AAV-LAV-BPIFB4 gene transfer in aged mice reduced the pool of peripheral immunosenescent cells that were shown to be enriched in the spleen. In addition, the proper tuning of the immune secretory phenotype (IL1βlow, IL6low, IL10high) associated with a significant reduction in SA-beta Gal-positive area of aorta from AAV-LAV treated mice.

At the functional level, the reduction of senescence-associated inflammation ensured sustained NAD+ levels in the plasma of AAV-LAV-BPIFB4 old mice by preventing CD38 increase in F4/80+ tissue-resident macrophages and Ly6Chigh pro-inflammatory monocytes of the spleen and bone marrow. Finally, to validate the clinical implication of our findings, we showed that Long-living-individuals (LLIs, older than 95 years), which delay CVDs onset, especially if LAV-carriers, were characterized by high NAD+ levels. In conclusion, the new senotherapeutic action of LAV-BPIFB4 may offer a valuable therapeutic tool to control aging and reduce the burden of its pathophysiological disorders, such as CVDs.

Link: https://doi.org/10.1038/s41419-022-04535-z

Eusocial species are characterized by reproductive and non-reproductive castes, such as the familiar division of queens and workers in common insect species. Eusociality is more common in insects and less so in other classes of life, although there are a few eusocial mammals, such as the naked mole-rat. For researchers who investigate the comparative biology of aging, one of the more interesting aspects of eusociality is that queens live longer than workers, many times longer in some species, while being genetically identical. Why is this?

Comparing very similar species with divergent life spans is a desirable starting point if trying to reverse engineer the relationship between metabolism and longevity. In principle divergence within the same species should be an even better option, further narrowing the search for relevant mechanisms.

These days the comparative biology of aging is becoming ever less an abstract field of pure scientific inquiry. Practical applications for human medicine likely lie ahead. Determining how any specific aspect of cellular biochemistry contributes to species longevity, or other desirable traits such as the ability to regenerate organs, might deliver the basis for human therapies. Or it might not; it is hard to say in advance whether any specific set of mechanisms could be ported over into our species, or even has any great relevance to our biochemistry.

How Can Ant and Termite Queens Live So Long?

A view of the animal world suggests that because reproduction and maintenance are both costly, animals simply can't maximize both. So the more energy and nutrients an individual invests in producing offspring, the faster it will probably age, and the shorter its life will be. Yet in social insects such as termites, ants, bees, and wasps, the queens appear to have found a way to have their cake and eat it. In many colonies, queens that lay hundreds of eggs every day can stay alive for years or even decades, while workers that never lay a single egg in their life will die after a few months.

Differences in the genetic code can't explain the unusual longevity of queens compared to workers. All workers are daughters of the queen and, in many cases, any of those daughters could have grown up to become queens themselves had they received the appropriate royal treatment when they were larvae. Since the queen is the only one in a colony laying eggs, colonies with long-lived queens are likely to grow larger and send forth more young queens to start new nests, as well as males to fertilize them. In other words, many scientists reason, there must have been strong selective pressure to keep the queen alive for as long as possible by evolving delayed aging.

To try to learn more about what enables the long life of queens in social insects, a team of researchers decided to compare the activity levels of various genes in termites, ants and bees - two species of each. In all, they studied 157 individuals, including insects of different ages as well as different castes. Unsurprisingly, the team found that genes that are known to play crucial roles in reproduction showed different activity patterns in queens than they did in sterile workers. Some of these genes, which carry instructions for making proteins called vitellogenins, were active in queens of all species.

The main role of vitellogenins is to support the production of yolk for the eggs. But some scientists suspect that vitellogenins may be doing more than that: In honeybees, at least, research has found that vitellogenins also function as antioxidants. If vitellogenins do the same thing in other social insects, they might contribute to the resistance of queens to oxidation. The team also found differences in the activity of genes involved in the prevention of oxidative damage or the repair of such damage, between queens and egg-laying workers compared with sterile workers. But the precise genes involved differed strongly from one species to another. Apparently, each species has evolved its own way of keeping its queens alive longer.

This somewhat bewildering variety across species reveals an important lesson about the nature of aging: There isn't one button or switch that allows a species to invest more, or less, in maintenance or reproduction, but a whole dashboard of them that is set up slightly differently in each species.

Comparative transcriptomic analysis of the mechanisms underpinning ageing and fecundity in social insects

The exceptional longevity of social insect queens despite their lifelong high fecundity remains poorly understood in ageing biology. To gain insights into the mechanisms that might underlie ageing in social insects, we compared gene expression patterns between young and old castes (both queens and workers) across different lineages of social insects (two termite, two bee and two ant species). After global analyses, we paid particular attention to genes of the insulin/insulin-like growth factor 1 signalling (IIS)/target of rapamycin (TOR)/juvenile hormone (JH) network, which is well known to regulate lifespan and the trade-off between reproduction and somatic maintenance in solitary insects.

Our results reveal a major role of the downstream components and target genes of this network (e.g. JH signalling, vitellogenins, major royal jelly proteins and immune genes) in affecting ageing and the caste-specific physiology of social insects, but an apparently lesser role of the upstream IIS/TOR signalling components. Together with a growing appreciation of the importance of such downstream targets, this leads us to propose the TI-J-LiFe (TOR/IIS-JH-Lifespan and Fecundity) network as a conceptual framework for understanding the mechanisms of ageing and fecundity in social insects and beyond.

Lygenesis works towards restoration of liver function by implanting liver organoids into lymph nodes, where they survive and undertake many of the normal functions of a liver. People have more lymph nodes than needed in many parts of the body, so some can be sacrificed in this way to gain improved function. This approach is in clinical development, and the company plans to attempt much the same process for the thymus, another important organ in which function does not depend all that much on location in the body. Researchers associated with Lygenesis here explore other parts of the body that are amenable to hosting implanted organoids, expanding the options for this class of therapy.

Hepatocyte transplantation holds great promise as an alternative approach to whole-organ transplantation. Intraportal and intrasplenic cell infusions are primary hepatocyte transplantation delivery routes for this procedure. However, patients with severe liver diseases often have disrupted liver and spleen architectures, which introduce risks in the engraftment process. We previously demonstrated intraperitoneal injection of hepatocytes as an alternative route of delivery that could benefit this subpopulation of patients, particularly if less invasive and low-risk procedures are required; and we have established that lymph nodes may serve as extrahepatic sites for hepatocyte engraftment. However, whether other niches in the abdominal cavity support the survival and proliferation of the transplanted hepatocytes remains unclear.

Here, we showed that hepatocytes transplanted by intraperitoneal injection engraft and generate ectopic liver tissues in fat-associated lymphoid clusters (FALCs), which are adipose tissue-embedded, tertiary lymphoid structures localized throughout the peritoneal cavity. The FALC-engrafted hepatocytes formed functional ectopic livers that rescued tyrosinemic mice from liver failure. Consistently, analyses of ectopic and native liver transcriptomes revealed a selective ectopic compensatory gene expression of hepatic function-controlling genes in ectopic livers, implying a regulated functional integration between the two livers. Thus abdominal FALCs are essential extrahepatic sites for hepatocyte engraftment after transplantation and, as such, represent an easy-to-access and expandable niche for ectopic liver regeneration when adequate growth stimulus is present.

Link: https://doi.org/10.1002/hep.32277

Sourcing organs from genetically engineered pigs is one of the options under development for the production of organs on demand for patients who need transplants. Ethically, growing organs from cells would be a better option, but we live in a world in which animals are widely seen only as tools to be used and consumed; one might hope that our descendants will grow to be better than us in that regard. Major surgery is a high risk undertaking in older people, and the best of all options would be to find ways to spur controlled regrowth and repair in native tissues. That remains more of an aspirational goal at this point, and engineered pigs already exist. Following on from a test of kidney transplants from pigs to brain-dead patients, researchers recently successfully transplanted an engineered porcine heart into a conscious human patient.

The first person to receive a transplanted heart from a genetically modified pig is doing well after the procedure. Physicians and scientists worldwide have for decades been pursuing the goal of transplanting animal organs into people, known as xenotransplantation. Last week's procedure marks the first time that a pig organ has been transplanted into a human who has a chance to survive and recover. In 2021, surgeons transplanted kidneys from the same line of genetically modified pigs into two legally dead people with no discernible brain function. The organs were not rejected, and functioned normally while the deceased recipients were sustained on ventilators.

Xenotransplantation has seen significant advances in recent years with the advent of CRISPR-Cas9 genome editing, which made it easier to create pig organs that are less likely to be attacked by human immune systems. The latest transplant used organs from pigs with ten genetic modifications. The researchers had applied to the US Food and Drug Administration (FDA) to do a clinical trial of the pig hearts in people, but were turned down. The agency was concerned about ensuring that the pigs came from a medical-grade facility and wanted the researchers to transplant the hearts into ten baboons before moving on to people.

But a 57-year-old patient team a chance to jump straight to a human transplant. The patient had been on cardiac support for almost two months and couldn't receive a mechanical heart pump because of an irregular heart beat. Neither could he receive a human transplant, because he had a history of not complying with doctors' treatment instructions. Given that he otherwise faced certain death, the researchers got permission from the FDA to give the patient a pig heart.

For now, transplantation is limited by the supply of pigs as well as regulatory hurdles. There is currently just one company - Revivicor, owned by United Therapeutics - that has suitable facilities and clinical-grade pigs. To make the pig heart used in the transplant, the company knocked out three pig genes that trigger attacks from the human immune system, and added six human genes that help the body to accept the organ. A final modification aims to prevent the heart from responding to growth hormones, ensuring that organs from the 400-kilogram animals remain human-sized.

Link: https://www.nature.com/articles/d41586-022-00111-9

It is becoming clear that many first generation cell therapies are limited in efficacy by the mixing of cell populations and exhaustion of cells in culture. Many widely used stem cell therapy protocols, for example, may generate significant numbers of senescent cells in the process of preparing cells for injection. Small differences in protocol and implementation may produce large differences in outcome. Injecting senescent cells along with therapeutic cells is undesirable, and in addition to being directly harmful in any significant number, the presence of senescent cells during preparation of the therapy likely negatively impacts the beneficial characteristics of the other cells.

The situation becomes more complex for cell therapies that use immune cells. The immune system is a dynamic network of shifting cell behaviors and capabilities, adaptive to circumstances. Within any broad category of immune cell, such as T cells, monocytes, and so forth, individual cells are capable of adopting a wide range of states, and changing their states and behaviors quickly in response to circumstances. It is perhaps not surprising to find that these forms of cell therapy can be optimized dramatically, given the right approach to selecting only the desired cells, or at least excluding those that are most unhelpful.

Tumors dramatically shrink with new approach to cell therapy

People have been cured in the clinic of advanced melanoma through treatment with their own immune cells that were harvested out of tumor tissue. The problem is, because of the way the cells are harvested, it only works in a very small number of patients. The cells of interest, called tumor-infiltrating lymphocytes (TILs), are natural immune cells that invade tumor tissue. In cell therapies used in clinics today a mixture of "exhausted" and "naïve" cells is used to treat tumors. After they are extracted from tissue, cells are grown in labs far away from the patients they were harvested from. By the time they've multiplied and are ready to be placed back in the body, many of the cells are exhausted and unable to fight, having been in the tumor for too long.

Using a new technology called microfluidic affinity targeting of infiltrating cells (MATIC), researchers can pinpoint which cells are most active through cell sorting techniques enabled with nanotechnology. Scientists used MATIC to find what the authors called the "Goldilocks population" of cells, producing dramatic results for the mice population they were looking at. Tumors in mice shrank dramatically - and in some mice disappeared completely - producing a large improvement in survival rates compared to more traditional methods of TIL recovery.

Efficient recovery of potent tumour-infiltrating lymphocytes through quantitative immunomagnetic cell sorting

Adoptive cell therapies require the recovery and expansion of highly potent tumour-infiltrating lymphocytes (TILs). However, TILs in tumours are rare and difficult to isolate efficiently, which hinders the optimization of therapeutic potency and dose. Here we show that a configurable microfluidic device can efficiently recover potent TILs from solid tumours by leveraging specific expression levels of target cell-surface markers. The device, which is sandwiched by permanent magnets, balances magnetic forces and fluidic drag forces to sort cells labelled with magnetic nanoparticles conjugated with antibodies for the target markers.

Compared with conventional cell sorting, immunomagnetic cell sorting recovered up to 30-fold higher numbers of TILs, and the higher levels and diversity of the recovered TILs accelerated TIL expansion and enhanced their therapeutic potency. Immunomagnetic cell sorting also allowed us to identify and isolate potent TIL subpopulations, in particular TILs with moderate levels of CD39 (a marker of T-cell reactivity to tumours and T-cell exhaustion), which we found are tumour-specific, self-renewable and essential for the long-term success of adoptive cell therapies.

This open access paper is not so easy to summarize. It is a tour of some of the details by which immune system aging provokes chronic inflammation and fibrosis, the harmful deposition of scar-like structures rather than successful tissue maintenance. All of the mentioned details interact with one another, and all of the mentioned details matter. The primary focus of the authors is the liver, an organ in which inflammation and fibrosis play significant and well-studied roles in aging and disease, but the discussion is applicable more broadly. The lesson to take from this is that rejuvenation of the aged immune system is an important goal, given the negative impact it has throughout the body.

Almost all mature cells that undergo apoptosis in an age-dependent or an accidental manner are completely recovered in tissue-specific microenvironments without any physiological changes. After peripheral blood leukocytes are released into the local region, fibroblast cells and new blood vessels commonly proliferate during wound healing. Inducible repair tools mainly supplied from blood vessels are cleared by peripheral blood phagocytic macrophages. Finally, hematopoietic stem cell (HSC)-derived precursor cells migrate from bone marrow (BM) to the microenvironment to rebuild damaged tissues.

In this review, we question how to control inflammation and fibrosis in older patients with lifestyle-related diseases, including NASH. We now propose the alternative inflammation and fibrosis pathway in CD40+ endothelial cells in hepatic sinusoids (HSECs) other than the main fibrosis pathway in HSCs. We suggest that HSCs are activated by bone marrow derived macrophages following the cell-cell interaction between senescent hepatocytes and senescent HSECs. However, the physiological condition of HSCs in a NASH-specific environment with chronic inflammation is still unclear. Therefore, it is very difficult to obtain a direct strategy for treating HSCs. Conversely, we hypothesized that senescent CD40+ HSECs are activated by CD154 on infiltrating senescent Th2 cells. This activation is enhanced by the cell-cell interaction among senescent hepatocytes, senescent HSECs, and senescent Küpffer cells.

Recently, the removal of senescent cells (senolysis) has been proposed for the treatment of lifestyle-related diseases. Kidney-type glutaminase (KGA) expression is increased according to low pH by lysosomal membrane damage. This induces an enhancement of the glutaminase 1 (GLS1) gene to maintain senescent cells. Senolysis induced by a GLS1 inhibitor rescues inflammation in lifestyle-related diseases. Therefore, we propose an alternative fibrosis pathway involving the cell-cell interaction of senescent cells in a NASH-specific environment with chronic inflammation at old age. Further examination is needed to determine how to control inflammation and fibrosis in older patients with lifestyle-related diseases, including NASH.

Link: https://doi.org/10.3389/fphys.2021.795508

Researchers here report on a promising advance in making a non-regenerative species more regenerative. In recent years, research has focused on differences in the behavior of macrophages and injury-induced senescent cells in those species capable of regeneration of organs. It is presently thought likely that the capability for regeneration of organs exists in all higher animals, but it is in some way suppressed after embryonic development. Thus suitable coercion of cell behavior may unlock this ability. In this case, applying a combination of growth factors and other compounds for a short period of time sufficiently changed cell behavior to induce limb regrowth in a frog species not normally capable of this feat. The result was not a fully formed limb, but there was more than enough regrowth of structure to suggest that this approach is worthy of further development.

Limb regeneration is a frontier in biomedical science. Identifying triggers of innate morphogenetic responses in vivo to induce the growth of healthy patterned tissue would address the needs of millions of patients, from diabetics to victims of trauma. Organisms such as the African clawed frog (Xenopus laevis) - whose limited regenerative capacities in adulthood mirror those of humans - are important models with which to test interventions that can restore form and function.

Here, we demonstrate long-term (18 months) regrowth, marked tissue repatterning, and functional restoration of an amputated Xenopus laevis hindlimb following a 24-hour exposure to a multidrug, pro-regenerative treatment delivered by a wearable bioreactor. The treatment used 1,4-dihydrophenonthrolin-4-one-3carboxylic acid (1,4-DPCA), brain-derived neurotrophic factor (BDNF), growth hormone (GH), resolvin D5 (RD5), and retinoic acid (RA).

Regenerated tissues composed of skin, bone, vasculature, and nerves significantly exceeded the complexity and sensorimotor capacities of untreated and control animals' regeneration. RNA sequencing of early tissue buds revealed activation of developmental pathways such as Wnt/β-catenin, TGF-β, hedgehog, and Notch. These data demonstrate the successful "kickstarting" of endogenous regenerative pathways in a vertebrate model.

Link: https://doi.org/10.1126/sciadv.abj2164

Senescent cells accumulate with age in tissues throughout the body, but their numbers remain small in comparison to somatic cells that continue to function. Nonetheless, lingering senescent cells produce a sizable harmful effect on cell and tissue function via the signaling molecules that they generate, the senescence-associated secretory phenotype (SASP). The SASP promotes growth and inflammation, and is beneficial in the short term scenarios of wound healing or cancer suppression. When present for the long term, these same signals become very disruptive.

The SASP is far from fully mapped, consisting of many different molecules, some secreted directly and many more packaged into extracellular vesicles. Researchers have so far largely focused their work on a few obvious suspects that seem likely to be more important. Of particular interest are a number of inflammatory cytokines, such as TGF-β, well-studied in other contexts. TGF-β is already a target for anti-inflammatory therapies. The connection to cellular senescence only makes it more attractive.

Today's open access preprint paper presents evidence for TGF-β to be important in one of the more insidious characteristics of senescent cells, their ability to encourage other cells to also become senescent. This isn't just a local phenomenon. Given sufficient TGF-β signalling, the burden of cellular senescence can be increased in distant tissues. This form of systemic inflammatory signaling is thought to be an important factor in the progression of aging, and researchers are looking into ways to disrupt TGF-β-induced senescence and inflammation.

Inter-organ transmission of hepatocellular senescence induces multi-organ dysfunction through the TGFβ signalling pathway

Cellular senescence is a state of permanent cell cycle arrest accompanied by a hyper-secretory phenotype (Senescence-Associate Secretory Phenotype, or SASP), and is associated with both injury and aging-related pathologies within affected organs. Removal of senescent cells is beneficial to both organ function and organism survival. Severe acute injury of any large organ is associated with systemic effects including multi-organ failure, of which acute liver failure (ALF) is a paradigm. ALF is itself associated with senescence induction and subsequent regenerative failure. Studies both in vitro and in vivo have shown that senescence can be transmitted in a paracrine manner within affected organs, however whether senescence can spread systemically to more distant organs remains unknown.

Here we use acute liver senescence as an exemplar model, independent of systemic aging, to test whether senescence can be transmitted between organs in an endocrine manner. The SASP is a central mediator of the non-autonomous effects of senescent cells. We present evidence that senescence can be transmitted to and affect the function of distant organs in a systemic manner. In the context of acute injury, senescence has often been described as part of a finely-tuned mechanism with overall beneficial effects for wound healing. As described by others, SASP factors are able to induce reprogramming in neighbouring cells, facilitating tissue regeneration. However, following severe injury, this mechanism may have the opposite effect, through excessive SASP production, including senescence- and reprogramming-inducing factors. This excess of SASP factors may enter the circulation and induce widespread senescence and reprogramming to distant organs. In turn, this excessive stimulus for senescence, re-programming and regeneration can compromise organ function.

Systemic transmission of senescence may be relevant to several diseases. Here we use a model of hepatocyte-specific senescence to model an acute senescence phenotype, such as the one observed during ALF. ALF is itself characterised by sequential multi-organ failure typically beginning with the kidney and also involving the brain and lung in addition to other organs. This clinical progression may, at least in part, be underpinned by the systemic transmission of senescence. The observation that TGFβ signalling is a central driver of systemic transmission of senescence paves the way for new therapeutic approaches in diseases where this phenomenon occurs. This is in line with the beneficial effects of senolytics and senomorphics that have been elegantly demonstrated on numerous pathologies.

Chronic inflammation in aging drives the onset and progression of many age-related conditions. Researchers here focus on arthritis, but their findings are probably applicable to numerous other issues in aging. The gut microbiome changes with age in ways that promote the growth of inflammatory microbial species, and this may be an important component of age-related inflammation. Researchers here dig into some of the complexity of the microbiome, in search of points of intervention.

Researchers have discovered that a protein naturally present in the gut acts on the microbiota and causes the formation of molecules that exacerbate the symptoms of these diseases. The protein in question, phospholipase A2-IIA, was discovered several years ago in the fluid that surrounds the joints of people with arthritis. The protein was subsequently detected elsewhere in the body, notably in the gut where it is produced in abundance. "It took a long time before we realized that it exhibits antibacterial activity. The protein interacts little with the membrane of human cells, but it has high affinity for bacterial membranes. It binds to these membranes and splits them, releasing small molecules such as fatty acids."

To study the effect of this protein on gut microbiota, researchers used a line of transgenic mice. These mice have the human gene that codes for phospholipase A2-IIA. As they age, they spontaneously develop manifestations of chronic systemic inflammation. Experiments on these mice revealed that phospholipase alters the profile of bacterial lipids that end up in the gut. By releasing fatty acids from the bacterial membranes, the protein produces proinflammatory lipids that exacerbate chronic inflammation and increase the severity of arthritis symptoms in these mice.

These breakthroughs could have therapeutic implications, he says. "The work of both teams suggests that local inhibition of phospholipase may alleviate the inflammatory process that exacerbates certain diseases. It also suggests that blocking the bacterial proinflammatory lipids produced in the gut by this protein could reduce symptoms in people with systemic inflammatory diseases. The next step in our work is to test these ideas in patients with arthritis."

Link: https://www.eurekalert.org/news-releases/941123

Researchers here measure mitochondrial function in older people and find that those with less functional mitochondria are more prone to physical aspects of frailty, such as loss of mobility resulting from muscle weakness. Sarcopenia, the loss of muscle mass and strength with age, may largely result from loss of muscle stem cell activity, and mitochondrial dysfunction with age may be an important contributing cause of stem cell decline. That said, all of the aspects of aging tend to move in unison in any one individual, and independent mechanisms of aging form a loosely interact web of cause and consequence. An observed correlation between any two aspects of aging doesn't necessarily imply direct and meaningful causation.

Slow gait and mobility decline are common in older age and are associated with adverse outcomes such as mobility disability, reduced quality of life, loss of autonomy in daily life activities, and mortality. Such a decline may arise from impairments in the central nervous system (CNS), musculoskeletal system, and metabolic systems. Previous findings suggest that age-related decline of mitochondrial function may contribute to loss of mobility. Compared to young adults, older adults have lower skeletal muscle oxidative capacity and higher metabolic cost of walking.

Proposed mechanisms underlying the relationship between mitochondrial dysfunction and mobility decline include impairments in energy production and energy utilization. Energy production can be impaired due to age-related decline of mitochondrial function, possibly through a combination of lack of energy, increased oxidative stress, oxidative damage to mitochondrial DNA and the complexes of the electron transport chain, and altered gene expression.

We examined 380 cognitively normal participants aged 60 and older who were well-functioning (gait speed ≥ 1.0 m/s) and free of Parkinson's disease and stroke at baseline and had data on baseline skeletal muscle oxidative capacity and one or more mobility assessments during an average 2.5 years. Muscle oxidative capacity was measured by phosphorus magnetic resonance spectroscopy as the post-exercise recovery rate of phosphocreatine (kPCr). Mobility was measured by four walking tests.

Lower baseline kPCr was associated with greater decline in all four mobility measures. Thus among initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. The longitudinal relationship between skeletal muscle mitochondrial function and mobility decline appeared to be mediated by the change in thigh muscle strength, lean mass, and fat mass.

Link: https://doi.org/10.1111/acel.13552

Venture capitalists are characterized as exhibiting sheep-like behavior, though it would probably be more correct to say that the limited partners who invest in venture funds have this issue, and the venture capitalists must go along with it if they want to build a fund at all. Investment organizations are risk-averse in interesting ways, and near always prefer to put funds into a near clone of an existing effort that has shown traction rather than something novel. With this in mind, I'll note that a sizable fraction of companies in the longevity industry are drug discovery platform developers whose founders happen to favor mechanisms of aging as a target. The companies typically launch with only a declared agenda and the start of a platform intended to make small molecule drug discovery more efficient in some way; usually this involves machine learning.

To what degree are these companies multiplying because it is comparatively easy to raise funds with this pitch, versus this being a period of time in which advances in machine learning are genuinely offering many ways in which to meaningfully improve small molecule drug discovery? I'm not familiar enough with that part of the field to comment. Either way, work on aging seems like it might be something of an afterthought in the underlying mechanisms that have produced a prevalence of these initiatives. The iconic example of a computational drug discovery platform company in the longevity industry is Insilico Medicine, now largely pivoted away from aging in favor of selling capabilities in drug discovery to industry giants. On the other hand, BioAge appears to be staying the course to put some of their drugs into clinical trials. Gero could yet go either way. And so forth.

An any case, that said, Arda Therapeutics is another new drug discovery platform company that launched with big name seed stage investors, and a good philosophy of development related to selective destruction of problem cells in the aging body. There are many populations of cells that are small in number but cause outsized issues, particularly in the immune system, such as age-associated B cells, chronically activated microglia, and so forth. There are likely more such cell types yet to be discovered. On the whole, not much has been done to advance the practical removal of these cells to the clinic, outside the cancer and senolytics research and development communities. This is an area in which more initiatives are needed.

Arda Therapeutics: Targeting Cells to Treat Disease

Today, I'm excited to introduce Arda Therapeutics. Arda is taking aim at chronic diseases and aging by eliminating the pathological cells that drive these conditions. Our approach starts by using single-cell data to identify pathological cells and specific markers to target them. We then design therapies to eliminate these - and only these - cells. We are initially focused on treating chronic diseases, with the long-term goal of extending healthy lifespan.

The idea of eliminating - or "targeting" - bad cells is not new; most cancer treatments are based on this strategy. Yet when it comes to other diseases, rather than removing harmful cells, most therapeutics modulate the activity of individual proteins with the goal of modifying cell behavior. However, cell behavior is a consequence of complex regulatory networks: multiple pathways contribute, often with redundancy, making cell behavior difficult to change via single targets. We believe that in many cases the better strategy is to eliminate the entire pathological network - that is, the entire cell.

Our team combines expertise in pathological cell clearance with a rare blend of computational and drug development know-how. Still, there is no guarantee of success. Ten years from now, I believe there will be dozens of cell targeting therapeutics for chronic diseases. I hope many of them are Arda's. But if we fail at making successful drugs, we will at least succeed in mapping part of this new territory, making it a bit easier for others to take the next step. Ultimately, we are running the same relay race, and the trophy is more quality time for all of us.

It is always pleasant to see people publishing basically sensible thoughts about the treatment of aging as a medical condition. This short example is a good one: realistic, no hype, a sober assessment of the present state of development in academia and industry, yet still optimistic. We still need more of this sort of thing out there in the world, a beacon of common sense to counteract the nonsense-ridden, low-value discussions of aging that are still prevalent in the media whenever the topic arises.

Of the 150,000 deaths that occur on Earth every day, over two thirds of them are due to ageing. This is because, biologically, the ageing process is the cause of our biggest killers, like cancer, heart disease, and dementia. Though diet, lifestyle, and other factors can make these more or less likely, their effect is dwarfed by the biological consequences of getting older. Every so often, a study proposes a 'limit' on human lifespan, either by looking at demographic trends, or analysing aspects of human biology. However, these 'limits' have repeatedly been smashed historically, as life expectancy in the leading country has increased by three months per year, every year for almost two centuries.

Scientists have found dozens of ways to intervene in the ageing process in the lab. A lot of people imagine that living longer would mean extending the frail years at the end of life, dragging out our decrepitude. But this understandable worry gets things backwards from a biological perspective: as we treat ageing, we'd increase healthspan by deferring the age-related changes that cause disease, and this would cause people would live longer. Exceptionally long-lived humans don't just live longer, but spend a greater fraction of their lives in good health.

In spite of big-money bets from billionaires, it's not clear how long it will be before we can expect to see the first anti-ageing medicines in hospitals, or the local pharmacy. Moving from an idea that works in mice in the lab to human treatments is a notoriously difficult process. However, it seems likely that they will arrive in time for most people alive today. Front-runners, like senolytic drugs that remove aged, senescent cells from the body have proved their mettle in mice and are already undergoing human trials, so it's quite possible they could be in use before the decade is out. More speculative ideas, like the cellular reprogramming being explored by Altos Labs, might be decades away - but, if you're middle-aged or younger today, or a little older but live longer thanks to the first generation of anti-ageing drugs, a few decades is still soon enough to matter.

Link: https://www.polytechnique-insights.com/en/columns/health-and-biotech/true-false-uncertain-ageing/

We live in an age of comfort and engines of transport. As a result, few people exercise as much as they should in order to maintain optimal health. A sizable fraction of lost capacity with aging is due to sedentary behavior, as exhibited by studies showing that structured exercise programs can reduce mortality to a similar degree to widely used preventative medicine such as statins and antihypertensive drugs. The study noted here is another way of framing the well-known relationship between exercise and mortality in later life in our species: how many deaths would be avoided were people to exercise just a little more than is presently the case?

Previous studies suggest that a substantial number of deaths could be prevented annually by increasing population levels of physical activity. However, previous estimates have relied on convenience samples, used self-reported physical activity data, and assumed relatively large increases in activity levels (e.g., more than 30 minutes per day). The potential public health benefit of changing daily physical activity by a manageable amount is not yet known. In this study, we used accelerometer measurements (1) to examine the association of physical activity and mortality in a population-based sample of US adults and (2) to estimate the number of deaths prevented annually with modest increases in moderate-to-vigorous physical activity (MVPA) intensity.

This analysis included 4,840 participants. Increasing MVPA by 10, 20, or 30 minutes per day was associated with a 6.9%, 13.0%, and 16.9% decrease in the number of deaths per year, respectively. We estimated that approximately 110,000 deaths per year could be prevented if US adults aged 40 to 85 years or older increased their MVPA by a small amount (ie, 10 minutes per day). To our knowledge, this is the first study to estimate the number of preventable deaths through physical activity using accelerometer-based measurements among US adults while recognizing that increasing activity may not be possible for everyone. These findings support implementing evidence-based strategies to improve physical activity for adults and potentially reduce deaths in the US.

Link: https://doi.org/10.1001/jamainternmed.2021.7755