Fight Aging!

Conferences are a measure of the health of a field; typically the more conferences one sees, the broader the efforts and the larger the funding. Most of the best conferences relating to aging research, and the longevity industry that has emerged from that research, feature an even mix of entrepreneurs, scientists, and investors. The networking at these conferences leads to the foundation of new ventures and seed funding for young ventures. This is important in a field in which there are many, many opportunities to make progress. Networking makes the world turn; it is an essential part of the messy, human process of bringing new technology from the laboratory to the clinic.

Longevity industry and related, relevant conferences in the first half of this year were hectic and crowded close together in time, a result of the end of COVID-19 restrictions. Conference organizers tended to pack their delayed events into the March to June conference season. It has been a busy time for those of us who are obliged to attend! Now there will be a few months of pause before the conferences of interest resume in the later part of the year. Here, I'll note a few of the upcoming events that seem worth a look, or were interesting in past years.

Ending Age-Related Diseases 2022, August 11-14 2022, a Virtual Conference

We are delighted to announce the fifth Ending Age-Related Diseases conference on August 11-14, 2022! This virtual conference will bring together the leading experts in rejuvenation biotechnology and investment in order to foster scientific and business collaborations to develop rejuvenation therapies that target the root causes of aging.

ARDD 2022, August 29th to September 2nd 2022 in Copenhagen, Denmark

According to the United Nations, the proportion of people aged over 65 now outnumber children younger than 5. The enormous growth in the elderly population is posing a socioeconomic challenge to societies worldwide, and necessitates new sweeping interventions for age-associated diseases. This year we have an incredibly exciting program with global thought-leaders sharing their latest insights into aging and how we target aging process ensuring everyone lives a healthier and longer life. Welcome to the 9th Aging Research and Drug Discovery (ARDD) Meeting.

Longevity Summit Dublin, September 18-20 2022 in Dublin, Ireland

Join us for the Inaugural Longevity Summit in the capital city of Ireland. You will be experiencing a wonderful summit that includes a programme bursting with the "Who's Who" of longevity movement superstars, including George Church, Aubrey de Grey, Jim Mellon, and more. Gather with us for an informative, uplifting conference recognising and celebrating emerging research and developments across the Longevity Industry globally.

Longevity Investors Conference, September 28-30 2022 in Gstaad, Switzerland

The Longevity Investors Conference is the world's leading and most private longevity-focus investors only conference. LIC provides relevant insights into the longevity subject, expert education, investment opportunities, excellent networking opportunities and a great setting in an exclusive location. The two full days conference is bringing together the world's top longevity KOLs, institutional and private investors, wealthy private investors, family offices and funds.

Rejuvenation Startup Summit 2022, October 14-15 2022 in Berlin, Germany

The Rejuvenation Startup Summit, brought to you by the Forever Healthy Foundation, is a vibrant networking event that aims to accelerate the development of the rejuvenation biotech industry. Rejuvenation/Longevity biotech is a new, emerging field of medicine. It aims to prevent and reverse diseases of aging by addressing their common root cause, the aging process itself. Rejuvenation therapies aim to reverse or repair age-related cellular changes such as molecular waste, calcification, tissue stiffening, loss of stem cell function, genetic alterations, and impaired energy production. The Summit brings together startups, members of the longevity venture capital / investor ecosystem, and researchers interested in founding or joining a startup - all aiming to create therapies to vastly extend the healthy human lifespan.

The Longevity Forum, in Longevity Week, November 14-18 2022 in London

A step change in life expectancy, which is already underway and is being driven by both scientific and technological progress, will have vast implications for individuals, governments and society as a whole. To ensure that increases in longevity benefit all of society, a true public and private partnership is required to drive change and create solutions needed to equip us for this new reality. We actively engage with public and private sector stakeholders.

Eurosymposium on Healthy Ageing, November 24-26 2022 in Brussels, Belgium

The Eurosymposium on Healthy Ageing (EHA) is a unique biennial meeting of scientists working on the biology of ageing. The sixth EHA will happen in November (24 to 26) 2022. More information will follow!

Foresight Vision Weekend 2022, November 2022 in France and December 2022 in the US

Foresight Institute supports the beneficial development of high-impact technology to make great futures more likely. We focus on science and technology that is too early-stage or interdisciplinary for legacy institutions to support, for instance biotech to reverse aging. Save the date for Vision Weekend, Foresight Institute's annual member gathering. Collaborate across continents, disciplines, and generations towards flourishing futures. In 2022, we'll return with our favorite collaborators to our favorite venues: November 18-20 at Chateau du Fey, France, and December 02-04 at the Internet Archive in the Bay Area.

Researchers here outline a mechanisms by which the excess tau protein in the brain characteristic of Alzheimer's disease can interfere in the signaling between neurons that is necessary for cognitive function. Interestingly, they also suggest that a very similar mechanism is at play in the accumulation of α-synuclein in conditions such as Parkinson's disease. As always the question is always whether this mechanism is actually a meaningful contribution to the loss of function observed in patients. The brain is very complex, and neurodegenerative conditions are a mess of many, many seemingly harmful mechanisms. As the failure of past efforts to intervene in Alzheimer's disease indicates, not all of those mechanisms are important at any given stage of the condition.

A study has revealed how excess tau - a key protein implicated in Alzheimer's disease - impairs signaling between neurons in the brains of mice. The research began ten years ago, when researchers looked at the effect of high levels of soluble tau on signal transmission at the calyx of Held, the largest synapse in mammalian brains. Synapses are the places where two neurons make contact and communicate. When an electrical signal arrives at the end of a presynaptic neuron, chemical messengers, known as neurotransmitters, are released from membrane 'packets' called vesicles into the gap between neurons. When the neurotransmitters reach the postsynaptic neuron, they trigger a new electrical signal.

Using mice, the research team injected soluble tau into the presynaptic terminal at the calyx of Held and found that electrical signals generated in the postsynaptic neuron dramatically decreased. The scientists then fluorescently labelled tau and microtubules and saw that the injected tau caused new assembly of many microtubules in the presynaptic terminal. A second important clue was that elevated tau only decreased the transmission of high-frequency signals, while low-frequency transmission remained unchanged. High-frequency signals are typically involved in cognition and movement control. The researchers suspected that such a selective impact on high-frequency transmission might be due to a block on vesicle recycling. Vesicle recycling is a vital process for the release of neurotransmitters across the synapse since synaptic vesicles must fuse with the presynaptic terminal membrane, in a process called exocytosis. These vesicles are then reformed by endocytosis and refilled with neurotransmitter to be reused. If any of the steps in vesicle recycling are blocked, it quickly weakens high-frequency signals, which require the exocytosis of many vesicles.

While searching for a link between microtubules and endocytosis, the team realized that dynamin, a large protein that cuts off vesicles from the surface membrane at the final step of endocytosis, was actually discovered as a protein that binds to microtubules, although little is known about the binding site. When the scientists fluorescently labelled tau, microtubules, and dynamin, they found that presynaptic terminals that had been injected with tau showed an increase of bound dynamin, preventing the protein from carrying out its role in endocytosis. Finally, the team created many peptides with matching sequences of amino acids to parts of the dynamin protein, to see if any of them could prevent dynamin from binding to the microtubules, and therefore rescue the signaling defects caused by tau protein. When one of these peptides, called PHDP5, was injected along with tau, endocytosis and synaptic transmission remained close to a normal level.

Link: https://www.oist.jp/news-center/press-releases/untangling-role-tau-alzheimer%E2%80%99s-disease

As scientists note here, a number of reptilian and amphibian species exhibit negligible senescence, in that their mortality risk does not increase with age, at least not until very late life. The question has always been whether there is anything that can be learned from the cellular biochemistry of these species that can serve as the basis for enhancement therapies in mammals. There is no assurance that the basis of negligible senescence in any given species is simple enough to be useful. There is no assurance that even a simple difference could be safely ported over into mammalian biology given the biotechnology of the next few decades. Nonetheless, it is a topic of interest in the research community, a way to broaden the understanding of how differences in genetics and metabolism give rise to sizable differences in shape and length of life between species.

Researchers have documented that turtles, crocodilians, and salamanders have particularly low aging rates and extended lifespans for their sizes. The team also found that protective phenotypes, such as the hard shells of most turtle species, contribute to slower aging, and in some cases even "negligible aging" - or lack of biological aging. In their study, the researchers applied comparative phylogenetic methods, which enable investigation of organisms' evolution, to mark-recapture data in which animals are captured, tagged, released back into the wild and observed. Their goal was to analyze variation in ectotherm aging and longevity in the wild compared to endotherms (warm-blooded animals) and explore previous hypotheses related to aging, including mode of body temperature regulation and presence or absence of protective physical traits.

The thermoregulatory mode hypothesis suggests that ectotherms, because they require external temperatures to regulate their body temperatures and, therefore, often have lower metabolisms, age more slowly than endotherms, which internally generate their own heat and have higher metabolisms. The findings, however, reveal that ectotherms' aging rates and lifespans range both well above and below the known aging rates for similar-sized endotherms, suggesting that the way an animal regulates its temperature - cold-blooded versus warm-blooded - is not necessarily indicative of its aging rate or lifespan. The protective phenotypes hypothesis suggests that animals with physical or chemical traits that confer protection, such as armor, spines, shells or venom, have slower aging and greater longevity. The team documented that these protective traits do, indeed, enable animals to age more slowly and, in the case of physical protection, live much longer for their size than those without protective phenotypes.

Interestingly, the team observed negligible aging in at least one species in each of the ectotherm groups, including in frogs and toads, crocodilians and turtles. "It sounds dramatic to say that they don't age at all, but basically their likelihood of dying does not change with age once they're past reproduction. Negligible aging means that if an animal's chance of dying in a year is 1% at age 10, if it is alive at 100 years, it's chance of dying is still 1%. By contrast, in adult females in the US, the risk of dying in a year is about 1 in 2,500 at age 10 and 1 in 24 at age 80. When a species exhibits negligible senescence, aging just doesn't happen. Understanding the comparative landscape of aging across animals can reveal flexible traits that may prove worthy targets for biomedical study related to human aging."

Link: https://www.psu.edu/news/story/secrets-reptile-and-amphibian-aging-revealed

People who reach extreme old age do so because they managed to be less damaged and dysfunctional at every age than their now deceased peers. Why is this the case? A great deal of effort is devoted to answering that question, and I have mixed feelings on whether it is all that useful as a focus for the research community. For example, if genetic variants explain some of the survival of centenarians, then they don't have to be all that good. All it takes is a few percentage points of lowered mortality risk year after year provided by a given variant, and people at very advanced ages will largely have that variant. But a few percentage points are not worth chasing with large-scale investment into the development of drugs that mimic the effects of that variant.

More interesting is whether or not centenarian biochemistry confirms the importance of aspects of aging thought to be influential on mortality, such as the chronic inflammation that is characteristic of old age. The immune system runs down in later life, and a part of that dysfunction is the unresolved, harmful inflammation that is provoked by the signaling of senescent cells, by the DNA debris present in aged tissues, and by other, similar issues. The burden of inflammation varies widely by lifestyle choice and other less well explored characteristics of the individual. In today's open access paper, researchers discuss the evidence for centenarians to exhibit an immune system configuration that acts to suppress inflammation. Why this configuration arises in some people and not others is an open question.

Centenarians Alleviate Inflammaging by Changing the Ratio and Secretory Phenotypes of T Helper 17 and Regulatory T Cells

Inflammaging is suggested to be one of the major contributory factors leading to the increased morbidity and mortality of older adults; however, the inflammaging status, especially the subsets of CD4+ T cells in centenarians is not clearly understood. Herein, it was found that centenarians had unique levels of inflammatory cytokines and reduced Th17/Treg levels. CD4+ T cells in centenarians tended to differentiate into pro-inflammatory cells with decreased secretory function. These results suggested the presence of a mechanism in centenarians that alleviated inflammaging. This may be through the reversal of the imbalance of Th17/Treg cells and the reduction of pro-inflammatory cytokines.

Associated with immune dysregulation, inflammaging has been attributed to a combination of age-related defects. One of the most evident characteristics of inflammaging is high blood levels of pro-inflammatory mediators, including CRP, TGF-β, TNF-α, IFN-γ, IL-1, and IL-6, in the absence of evident triggers. The levels of these pro-inflammatory mediators have an important relationship with the processes of longevity and aging-related diseases and are positively correlated with mortality. In this study, we detected the levels of inflammation-related factors in the plasma of centenarians and demonstrated that many pro-inflammatory factors, namely, CRP, IL-12, TNF-α, IFN-γ, and IL-6, were elevated in centenarians. Intriguingly, other proinflammatory cytokines, such as IL-17A, IL-1β, and IL-23, were reduced in centenarians. This evidence suggested that centenarians partly alleviated inflammaging by affecting the secretion of these cytokines.

In vitro T cell cultures from different ages provided controversial results. We found that naive T cells of centenarians tended to differentiate into Th17 cells instead of Tregs, which was demonstrated in previous studies. Studies have shown that naive CD4+ T cells from aged animals differentiate into Th17 effectors more readily than T cells from young animals. This tendency of Th17 polarization seems to be an inherent characteristic of naive CD4+ T cells from older individuals. Furthermore, we demonstrated that they secreted fewer proinflammatory cytokines and relatively more anti-inflammatory cytokines. This was consistent with previous studies, and this phenomenon may be associated with altered metabolic activity.

Previous studies have found that CD4+ T cells in centenarians have a senescent pro-inflammatory phenotype. This study showed that centenarians had very specific changes in CD4+ T cell populations, which were manifested by an elevated Th17/Treg ratio in vivo, as well as a changed secretory phenotype. Although the T cells of centenarians cannot resist the aging-related expression of proinflammatory genes, their secretory phenotype was altered, explaining the relatively low level of inflammation in centenarians. These results suggested the presence of a mechanism to ameliorate inflammaging in centenarians. This may be achieved by reversing the imbalance of Th17/Treg cells and reducing pro-inflammatory cytokines.

Senescent cells accumulate with age throughout the body. They secrete a potent mix of signals that provoke chronic inflammation and dysfunction in cells and tissues. It is becoming increasingly clear that senescent cells are involved in brain aging, and clearance of senescent cells from the brain has been shown in animal studies to reduce chronic inflammation and pathology in the context of neurodegenerative conditions. Here, researchers argue that senescent cells are implicated in the early stages of the development of Parkinson's disease. This is a hypothesis that could be readily tested in humans, given funding for a clinical trial using the dasatinib and quercetin senolytic therapy. These therapeutics can pass the blood-brain barrier, have been assessed for their ability to clear senescent cells in the brain in animal studies, and are currently being trialed in Alzheimer's patients.

Immune responses are arising as a common feature of several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS), but their role as either causative or consequential remains debated. It is evident that there is local inflammation in the midbrain in PD patients even before symptom onset, but the underlying mechanisms remain elusive.

In this mini-review, we discuss this midbrain inflammation in the context of PD and argue that cellular senescence may be the cause for this immune response. We postulate that to unravel the relationship between inflammation and senescence in PD, it is crucial to first understand the potential causative roles of various cell types of the midbrain and determine how the possible paracrine spreading of senescence between them may lead to observed local immune responses. We hypothesize that secretion of pro-inflammatory factors by senescent cells in the midbrain triggers neuroinflammation resulting in immune cell-mediated killing of midbrain dopaminergic neurons in PD.

Link: https://doi.org/10.3389/fnagi.2022.917797

Alzheimer's disease, like all neurodegenerative conditions, is a complex and still incompletely understood disease. Many pathological mechanisms are involved, and it is far from clear as to which of them are more or less relevant at different stages of the progression of Alzheimer's disease. This poor understanding is well illustrated by the ongoing failure of clinical trials targeting removal of amyloid-β. The materials here are an interesting discussion of a pathological role undertaken by astrocytes in response to amyloid-β; it remains to be seen as to whether further evidence will show that this provides a significant contribution to loss of function in patients.

Star-shaped supporting cells in the brain, called astrocytes, are greatly involved in Alzheimer's disease and its progression. After studying basic cellular pathways and how they change in astrocytes, the researchers have identified the conversion of amyloid-beta to urea in the brain as an important mechanism. The urea cycle is widely studied and understood as a major metabolic pathway in the liver and kidneys, as a part of our digestive and excretory processes. Surprisingly, previous studies have reported increased urea in the brain of Alzheimer's disease patients, which led researchers to wonder if the urea cycle played any role in the pathology of the disease. To their surprise, they found that the urea cycle is 'switched on' in the astrocytes of the Alzheimer's disease brain, in order to clean up the toxic amyloid-beta aggregates and remove them in the form of urea.

However, this isn't as beneficial as it sounds. The group found that the switching on of the urea cycle causes the production of ornithine, another metabolite that accumulates in the cell and needs to be cleaned up. The hardworking astrocytes produce the enzyme ornithine decarboxylase 1 (ODC1) in this condition to deal with the accumulated ornithine and convert it to putrescine. This consequently increases the levels of neurotransmitter γ-aminobutyric acid (GABA), as well as toxic byproducts like hydrogen peroxide (H2O2) and ammonia in the brain. This ammonia further feeds back into the urea cycle and continues this process, causing more and more accumulation of toxic byproducts. High levels of GABA released by these astrocytes play an inhibitory action on neuronal transmission, contributing to the tell-tale loss of memory in Alzheimer's disease.

"For years, scientists have been debating about the beneficial and detrimental role of reactive astrocytes, and with the findings of this study, our group is able to clearly demarcate the beneficial urea cycle and the detrimental conversion of ornithine to putrescine and GABA, thereby providing evidence of the dual nature of astrocytes in Alzheimer's disease brain."

Link: https://www.eurekalert.org/news-releases/956475

Cancer is a corruption of growth. It is the processes of normal regeneration and tissue maintenance run wild, let loose from the usual state of careful regulation. One of the mechanisms by which many types of cancer prosper is via manipulation of the innate immune cells called macrophages, a type of myeloid cell, recruiting them to assist the cancer in many of the same ways that macrophages assist in regeneration and tissue maintenance. Solid cancer tissue contains large numbers of these tumor-associated macrophages.

Researchers are interested in finding ways to sabotage this relationship, particularly since macrophages are also capable of destroying errant cells, given the right prompts. Is it the case that tumor-associated macrophages could be reprogrammed into attacking every type of cancer that they have become a part of? Perhaps. Any approach to achieve that goal must be based on a better understanding of the interactions between cancerous cells and macrophages, however. That research is an ongoing project: today's scientific materials take a look at one of the less common cancers, and the mechanisms that this cancer employs to convert macrophages to the task of supporting its growth.

How Tumors Make Immune Cells 'Go Bad'

"Tumors recruit immune cells. These immune cells should be able to recognize and attack the tumor cells, but we found that the tumor cells secrete a protein that changes their biology, so instead of killing tumor cells they actually do the opposite." In comparing samples of a variety of soft-tissue sarcomas in humans and laboratory mice, researchers noted that most of these tumors have an abundance of immune cells called myeloid cells in their microenvironment. "It was striking that such a large percentage of the immune cells were myeloid cells, and we thought that since they obviously weren't killing the tumor cells, they must be doing something to promote tumor growth. And indeed, our analysis of tumor samples showed that many of the myeloid cells had adopted a tumor-promoting function."

To find out what was causing this change, investigators examined the proteins secreted by the tumor cells and the receptors on the surface of the myeloid cells - the elements cells use to communicate. "We examined the cross-talk between these two populations of cells. We found that the tumor cells expressed high levels of a protein called macrophage migration inhibitory factor (MIF), and that the myeloid cells had receptors to sense the MIF proteins. This makes them switch their biology and promote, rather than block, tumor growth." The investigators believe this information could be used to create novel therapies against soft-tissue sarcoma. A medication designed to stop cancer cells from expressing MIF could be tested in combination with existing therapies, for example, to see if it improves outcomes for patients.

Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity

The standard of care is unsuccessful to treat recurrent and aggressive soft-tissue sarcomas. Interventions aimed at targeting components of the tumor microenvironment have shown promise for many solid tumors yet have been only marginally tested for sarcoma, partly because knowledge of the sarcoma microenvironment composition is limited. We employ single-cell RNA sequencing to characterize the immune composition of a sarcoma mouse model, showing that macrophages in the sarcoma mass exhibit distinct activation states. Sarcoma cells use the pleiotropic cytokine macrophage migration inhibitory factor (MIF) to interact with macrophages expressing the CD74 receptor to switch macrophages' activation state and pro-tumorigenic potential. Blocking the expression of MIF in sarcoma cells favors the accumulation of macrophages with inflammatory and antigen-presenting profiles, hence reducing tumor growth. These data may pave the way for testing new therapies aimed at re-shaping the sarcoma microenvironment, in combination with the standard of care.

Microglia are innate immune cells of the brain, and their dysfunction is implicated in the progression of neurodegenerative conditions. Microglia become overly activated and inflammatory with age, likely a reaction to cell damage and dysfunction resulting from mechanisms of aging, as well as to a rising background level of chronic inflammatory signaling characteristic of the aged environment, which the microglia then amplify. Here, researchers discuss how these pro-inflammatory changes in the brain can influence the development of cardiovascular disease outside the brain.

Microglia, commonly known as brain-resident immune cells, are ubiquitously present in the central nervous system (CNS) and participate in the monitoring of the microenvironment. Microglia are abundant within the brain and comprise up to approximately 20% of the total glial cells. Microglia are involved in almost all brain diseases, including neurodegenerative diseases, traumatic brain injury, and mental illness. After activation, microglia can secrete pro-inflammatory and anti-inflammatory mediators and play a broad role during CNS injury.

The autonomic nervous system, which comprises the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), contributes to the regulation of cardiac function. Sympathetic outflow is controlled by key regions and neural circuits in the CNS. The imbalance between the SNS and PNS, especially the continuous activation of the SNS, is one of the main contributors to pathological cardiac remodeling. However, the upstream regulators of SNS activity remain largely unknown. Recently, studies have shown that microglia may play an important role in regulating SNS activities and cardiovascular function by releasing various substances, including cytokines, chemokines, and growth factors.

Increased neuroinflammation and sympathetic tone contribute to the incidence and maintenance of hypertension. Additionally, after myocardial infarction, microglial activation in the hypothalamus has been observed, and increased levels of pro-inflammatory cytokines in the PVN then activate the hypothalamus-pituitary-adrenal axis, increase the activity of the sympathetic nervous system and contribute to the acute pro-inflammatory response in the myocardium after myocardial infarction. In summary, microglia play an important role in the crosstalk between the CNS and the peripheral nervous system, and interventions targeting microglia may represent promising potential therapies for cardiovascular diseases, including hypertension, myocardial infarction, heart failure, cardiac ischemia/reperfusion and ventricular arrhythmias.

Link: https://doi.org/10.2147/JIR.S350109

Accumulation of senescent cells is an important aspect of degenerative aging. While never present in very large numbers, relative to the overall count of all cells in a tissue, senescent cells generate a potent mix of signals that induce inflammation and disrupt normal tissue maintenance and function. Clearance of senescent cells via senolytic therapies is the presently favored approach to this issue, but a sizable faction in the research community are instead interested in suppression of senescent cell signaling. Research into the detailed biochemistry of senescence may lead in either direction, both of which can give rise to potential new therapies.

Several studies have reported the potential of epigenetic regulation in delaying senescence. Our previous studies showed that UV irradiation decreased HDAC4 expression in primary human dermal fibroblasts, and HDAC4 expression was reduced in aged skin in vivo. These results suggest that HDAC4 may play an important role in skin aging. However, there is a paucity of research on how HDAC4 causes skin aging.

By integrating our RNA-Seq data and previously reported transcriptome datasets from UV- and H2O2-induced senescence models, we identified DDIT4 as a promising candidate target of HDAC4 involved in HDAC4-dependent epigenetic regulation of skin aging. DDIT4 regulates cell growth, oxidative stress, autophagy, mitochondrial function, and apoptosis. We found that DDIT4 expression was markedly reduced in aged skin in vivo, in replicative senescent HDFs, and in senescent fibroblasts under repeated H2O2 treatment or UV irradiation. HDAC4 expression was positively correlated with DDIT4, and also significantly decreased in aged skin in vivo.

Our data indicate that the knockdown of DDIT4 prevented the HDAC4-induced reduction of SA-β-gal in senescent cells. Moreover, DDIT4 overexpression could restore the senescence-associated alterations of senescence-associated secretory phenotype components such as IL-β, IL-6, IL-8, MMP-1, and CXCLs, as well as aging-related genes, suggesting that DDIT4 may contribute to the skin aging process by regulating senescence-associated microenvironments. Therefore, DDIT4, known as an important negative regulator of mTOR, may play an essential role in suppressing cell senescence by inhibiting mTOR activity or p21.

Link: https://doi.org/10.18632/aging.204118

My attention was drawn recently to an open access paper from earlier in the year that illustrates the magnitude of the difference between aging in early old age versus later old age. The causes of aging are comparatively simple forms of damage and disarray that emerge from the normal operation of metabolism, but because a living being is an immensely complicated system, even simple damage quickly spirals into complex consequences. Simple changes in a complex system produce complex outcomes. Aging greatly changes pace and character in its early stages versus its late stages, as chains of cause and consequence pile up, and damage interacts with damage. It accelerates, and dysfunction grows and changes in nature.

The work noted here looks at the transcriptome of aged mice, an assessment of which genes are being expressed, and to what degree. The differences between mice in early and late old age are sizable, and where it is understood as to what effects are produced by the differences in transcription, it connects to the usual concerns in aging: diminished function, increased inflammation, and so forth. This reflects what we see in our own species; there is a great deal of difference between a 60-year-old and an 80-year-old. The observed differences are built from changes in cell function, that emerge in response to rising levels of cell and tissue damage.

Different phases of aging in mouse old skeletal muscle

With a graying population and increasing longevity, it is important to identify life transitions in later years and recognize heterogeneity among older people. The term "late life" is broadly defined by encompassing a heterogeneous group of adults of 65 years and older; hence, it is further classified into "young-old" and "old-old" groups in the hope of identifying the group with a distinct vulnerability to certain chronic diseases and mental illnesses. Supportively, several studies have discerned a comprehensive difference across physical, cognitive, and psychosocial domains between the young-old (aged 60 - 74 years) and old-old (aged 75 years and older) groups. A similar distinction may exist for physiological and pathological domains, such as chronic illnesses (cardiovascular disease, cancer, chronic respiratory diseases, and diabetes, among others) and the deterioration of skeletal muscle and cognitive function. In reality, these age-related illnesses vary markedly and can, with age, take the shape of a comorbidity, which is the co-existence of two or more diseases. For instance, only 30% of adults aged 45 - 64 years have at least two chronic conditions, whereas 65% of those aged 65 - 84 years and approximately 80% of those aged 85 years and older have the same conditions. Therefore, to investigate these age-associated diseases, it may be beneficial to divide the elderly into groups and inspect the resultant subgroups separately for pathophysiological differences, and other deteriorations or weaknesses.

In the case of mice, those ranging from 18 to 24 months-of-age, which is comparable to humans of 56 - 69 years-of-age, fulfil the requirements of "young-old" age, whereas mice aged 26 months and older can be considered as "old-old". It is notable that 22 - 24 months of age is when morphological changes consistent with human sarcopenia commence in mice and rats. This is the period skeletal muscle mass and grip strength decline progressively with age, exhibiting prominent changes at 24-28 months of age, while whole-body mass and lean mass were relatively stable or only marginally declined. Another significant distinction between the young-old and old-old groups is survivorship; 24- and 28-month-old mice exhibit 85% and 50% survival rates, respectively. Based on this rapid declines in muscle mass and survivorship with age, we assumed that aging accelerates in "late life" in a manner different from that in the slow aging mode before then. In addition to the increased morbidity and accelerated aging, we recently noticed that skeletal muscle in old-old mice, but not in young-old mice, underwent DNA demethylation particularly over genomic retroelements, and as a consequence, a large number of genomic retroelement copies acquire the competence for transcription. Similarly, the existence of other unexplored molecular and physiological traits that distinguish old-old mice from young-old mice, is also conceivable.

Using 24- and 28-month-old mice to represent the "young-old" and "old-old", respectively, we compared their skeletal muscle transcriptomes and found each in a distinct stage: early/gradual (E-aging) and late/accelerated aging phase (L-aging). The old-old transcriptomes were largely disengaged from the forward transcriptomic trajectory generated in the younger-aged group, indicating a substantial change in gene expression profiles during L-aging. The divergence rate per month for the transcriptomes was the highest in L-aging, twice as fast as the rate in E-aging. Indeed, many of the L-aging genes were significantly altered in transcription, although the changes did not seem random but rather coordinated in a variety of functional gene sets. Of 2,707 genes transcriptionally altered during E-aging, two-thirds were also significantly changed during L-aging, to either downturning or upturning way. The downturn genes were related to mitochondrial function and translational gene sets, while the upturn genes were linked to inflammation-associated gene sets.

Neuroinflammation, chronic and unresolved inflammation of brain tissue, is important in the progression of neurodegenerative diseases. It disrupts the normal maintenance and function of cells and tissue. As researchers note here, it is well know that the progression of atherosclerosis correlates with the progression of neurodegenerative disease. Atherosclerosis is the formation of fatty lesions that narrow and weaken blood vessels. It is an inflammatory condition, and atherosclerotic lesions are localized sites of inflammatory signaling and immune cell dysfunction. So it may well be that, in addition to more structural concerns around blood flow and rupture of vessels in the brain, that inflammatory signaling originating in blood vessel walls to some degree links these two conditions.

Neuroinflammation comprises inflammation-like processes inside the parenchyma of the central nervous system (CNS). Neuroinflammation is currently considered as a driving force in progression and likely etiology of numerous neurological diseases, including neurodegenerative ones. Atherosclerosis is a chronic disease characterized by progressive development of lipid-rich fibrotic deposits (atheroma plaques) inside the intima of large- and medium-sized arteries. Increasing evidence points to the chronic inflammation, occurring either locally or at the systemic level, as a key factor in progression of atherosclerotic lesions and related acute cardiovascular events.

Given the growing evidence pointing to the impact of systemic inflammation as a trigger of neuroinflammation, and the fact that neuroinflammation is recognized as being associated with neurodegenerative diseases such as Alzheimer's disease, it is important to assess neuroinflammation in the specific context of atherosclerosis in future studies. Indeed, the mechanistic link between atherosclerosis and neuroinflammation has barely been addressed so far, except in one experimental study on the animal model of atherosclerosis: the ApoE-knockout (ApoE-/-) adult mouse fed for 2 months with a hyperlipidic diet. In the brain of this atherosclerosis mouse model, reactive microglial cells and CD45+ infiltrated leukocytes significantly outnumbered microglia and leukocytes seen in age-matched, wild-type mice.

In this light, the mechanisms behind the atherosclerosis-related neuroinflammation still remain poorly understood, since the phenotypes of effector cells and the transcriptomic variations of inflammatory mediators have not been addressed so far.

Link: https://doi.org/10.3389/fnagi.2022.827263

TDP-43 is one of the small number of proteins that can misfold in ways that lead to aggregates and pathology. It is involved in a number of age-related neurodegenerative conditions, notably ALS. Like other aggregates found in the aging brain, such as amyloid-β, α-synuclein, and tau, TDP-43 aggregates are present in many older people. The decline into neurodegeneration is a sliding scale of pathology, in which some people, for reasons yet to be fully explored, develop much larger amounts of one or another protein aggregate than their peers. There is good reason to think that all protein aggregates are at least somewhat harmful and should be cleared, but as is the case in Alzheimer's disease, the damage done by some aggregates may be obscured by other, more severe forms of pathology that arise as the condition progresses.

The largest study to date on the prevalence of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) finds that this type of neuropathology is strikingly common among those who survive well into their 80s. The study integrated autopsy and cognitive data across 13 community cohorts that comprised more than 6,000 participants. Roughly half of people with amyloid-β plaques and tau tangles also had evidence of LATE-NC, whereas a quarter of people with little to no AD pathology had LATE-NC. Either neuropathological scourge alone was tied to cognitive impairment, but people who harbored both AD pathology and LATE-NC suffered the strongest cognitive blow.

About 40 percent of participants across the cohorts were cognitively normal at their last clinical visit, and roughly the same proportion had dementia. Fifteen percent reportedly had mild cognitive impairment. Across all of the cohorts, 39.4 percent of participants had evidence of LATE-NC. For cohorts that staged LATE-NC, about two-thirds had stage 2 or 3 pathology. In other words, about a quarter of all participants had stage 2/3 LATE-NC, which has been tied to cognitive impairment in previous studies.

How did LATE-NC relate to Alzheimer's disease pathology? Regardless of how the latter was measured, the main finding was the same: People with more severe Alzheimer's disease pathology, such as those with higher CERAD neuritic plaque scores or Braak stages, were more likely to also have LATE-NC. For example, while only a quarter of people with a CERAD score of "none" had LATE-NC, half of people with a CERAD score of "frequent" had this co-pathology. Notably, even among people without Aβ plaques, those with LATE-NC tended to have more extensive primary age-related tauopathy (PART).

Link: https://www.alzforum.org/news/research-news/later-you-think-tdp-43-pathology-lurks-40-percent-old-brains

Aortic stiffness occurs with age, and produces raised blood pressure, hypertension, by sabotaging the usual feedback mechanisms that control blood pressure. Hypertension in turn results in structural damage to delicate tissues throughout the body, as well as producing further biochemical changes that encourage ventricular hypertrophy, among other forms of dysfunction. It causes enough harm that control of blood pressure can meaningfully reduce mortality even without addressing underlying causes of degenerative aging.

Why do arteries stiffen with age? As today's open access paper discusses, this is in part a complex set of changes in the extracellular matrix of blood vessel walls, and in part dysfunction of the smooth muscle cells responsible for constriction and dilation of blood vessels. In the absence of ways to fully reverse one or other of these issues, it remains unclear as to how much of the problem is caused by each of these two contributions, but we can hope that this will change in the near future, given greater investment in research into the mechanisms of aging.

The structure and composition of the extracellular matrix defines the physical properties of a tissue, such as elasticity. With age, elastin laid down in youth becomes damaged and disordered, while other macromolecules that should slide past one another become cross-linked together by persistent advanced glycation end-products such as glucosepane. Meanwhile, inflammatory signaling and other forms of age-related biochemical dysfunction cause impairment in vascular smooth muscle, a failure to respond appropriately to signals to contract or dilate blood vessels.

Progressive aortic stiffness in aging C57Bl/6 mice displays altered contractile behaviour and extracellular matrix changes

As human life expectancy continues to grow, the incidence of age-related cardiovascular diseases (CVD) rises. CVD has long since become the leading cause of death, resulting in an estimated 17.9 million deaths each year (i.e., 30% of global death). Arterial stiffening - defined as the impaired capacity of the large elastic arteries to smoothen pulsatile blood flow - results in increased cardiac afterload, reduced coronary perfusion pressure, and pulsatile strain on the microcirculation. As such, arterial stiffness has gained much recognition as a hallmark and independent predictor of CVD.

Elastic arteries display a distinctly non-linear stiffness-pressure relation, with a limited increase in stiffness in the physiological pressure range but exponential increase at high distending pressure. Interestingly, despite pronounced variation in structural properties and vessel size across species, elastic modulus at mean physiological pressure is highly conserved across all vertebrate and invertebrate species with a closed circulatory system, suggesting strong evolutionary pressure.

In the present study, a longitudinal cardiovascular characterization of spontaneously (i.e., age-dependent) ageing C57Bl/6 mice is presented to establish the temporal relation of aortic stiffness to associated CVD, i.e., cardiac hypertrophy and peripheral hypertension. Furthermore, an in-depth physiological and biomechanical investigation of the isolated ex vivo thoracic aorta was employed to identify the key mechanisms of spontaneous arterial stiffening. We demonstrated that aortic stiffening precedes peripheral blood pressure alterations and left ventricular hypertrophy in spontaneously ageing C57Bl/6 mice, underlining the importance of implementing arterial stiffness measurement as an early marker of cardiovascular ageing in standard cardiovascular care.

Contraction-independent stiffening (due to extracellular matrix changes) is pressure-dependent. Contraction-dependent aortic stiffening develops through heightened α1-adrenergic contractility, aberrant voltage-gated calcium channel function, and altered vascular smooth muscle cell calcium handling. Endothelial dysfunction is limited to a modest decrease in sensitivity to acetylcholine-induced relaxation with age. Our findings demonstrate that progressive arterial stiffening in C57Bl/6 mice precedes associated cardiovascular disease. Aortic aging is due to changes in extracellular matrix and vascular smooth muscle cell signalling, and not to altered endothelial function.

This interesting paper notes that the difference in blood pressure assessed in left and right limbs correlates with measures arterial stiffening, but perhaps only in the legs rather than the arms. This is a consequence of human physiology, the structure of the circulatory system, and how stiffening affects control of blood pressure. The debate that the authors address is whether or not arms and legs are both relevant measurement sites on the body for this correlation. Their evidence points to ankle measurement of blood pressure as the more relevant site, and they theorize as to why this might be the case. It is all interesting! But as is true of a great deal of present day biometrics relating to aging, the purpose of rejuvenation research, such as those parts of the field that might ultimately eliminate arterial stiffening, is to render all of these measurements and considerations irrelevant.

In this population-based study using a simultaneous measurement of blood pressure and arterial stiffness, we evaluated the association between contralateral systolic blood pressure (SBP) differences and arterial stiffness by pulse wave velocity (PWV). We found that the prevalence of interankle differences in SBP of ≥10 mmHg and ≥15 mmHg were common, namely 25% and 12%. Our findings showed that higher body mass index (BMI), and lower ankle-brachial index (ABI) were significantly correlated to greater interarm SBP differences, while increased age, higher BMI, lower ABI, and greater contralateral differences in PWV were significantly correlated to greater interankle SBP differences.

Previous studies indicated SBP differences between arms carry prognostic information and that patients should have evaluation of blood pressure in both arms. In addition, the ankle has been suggested as an alternative and/or additional site for noninvasive blood pressure measurement. In the present study, blood pressure was measured simultaneously, bilaterally at both limbs. Compared with sequentially repeated measurements of blood pressure with a single-cuff that is typically conducted, the simultaneous measurement may be more precise as beat-by-beat differences in blood pressure can be accounted for and can improve diagnostic accuracy. Although brachial SBP was significantly associated with ankle SBP, interarm differences in SBP were not related to interankle differences in SBP suggesting that these contralateral differences in blood pressures may be modulated by different factors. Indeed, arterial stiffness was associated with interankle, but not with interarm, differences in SBP in the present study.

What are the explanations for the contribution of arterial stiffness to interankle SBP difference but a lack thereof to interarm differences? Arterial stiffening is a principal determinant of SBP and has been independently associated with stroke, coronary disease severity, and cardiovascular outcome. As the arterial wall stiffens, arterial wave reflection is a primary mechanism responsible for augmenting SBP. In the arterial tree, branching points, areas of alteration in arterial elastance (from elastic artery to muscular artery), and high-resistance arterioles can all give rise to wave reflection and the lower body is believed to be an important site of wave reflection. This cumulation of reflected waves along with the longer distance of the arterial tree to the ankle versus the upper arm is the reason that SBP at the level of the ankles is elevated in comparison to pressures measured in the arms in healthy humans. It appears plausible that contralateral differences in SBP may be influenced to a greater extent by the stiffness of arteries in the ankle.

Link: https://doi.org/10.1111/jch.14493

Inflammaging describes the raised, unresolved inflammation characteristic of old tissues, a dysfunction of the immune system that in turn produces failures of tissue maintenance and function. It arises from issues such as the inflammatory signaling of senescent cells and the reaction of the innate immune system to DNA debris from age-damaged cells. That senescent cells can be cleared, and that clearance will soon enough become a part of everyday medicine, means that the burden of inflammaging for future generations will be diminished. As a result, many age-related diseases will be reduced in incidence and severity, including atherosclerosis.

An increasing number of reports show that aging is a driving factor of atherosclerosis. Aging is closely related to endothelial dysfunction and arterial stiffness, which are considered to be early events leading to CVD. The aging process involves promotion of a series of risk factors (i.e., oxidative stress, endothelial dysfunction, and pro-inflammatory cytokines), leading to endothelial dysfunction and vascular system damage. In addition, cellular aging induces the release of microvesicles, further contributing to the development and calcification of atherosclerotic plaques. Therefore, the incidence of atherosclerosis increases with chronological age, and accelerated aging is the main risk factor for the development of atherosclerotic plaques. Furthermore, atherosclerotic plaques represent a key index of cellular aging, which is characterized by reduced cell proliferation, increased DNA damage, and telomere shortening. In summary, a growing body of evidence indicates that atherosclerosis is promoted by cellular aging.

Atherosclerosis is closely related to inflamm-aging, along with oxidative stress, endothelial dysfunction, and inflammation. Inflamm-aging is defined as a chronic inflammatory process during aging and mainly characterized by chronic progressive strengthening of the pro-inflammatory response. In other words, inflamm-aging promotes the body's pro-inflammatory status with advancing aging, which is closely related to many aging diseases. A series of studies have shown that aging can promote atherosclerosis by damaging the connection between mitochondrial function and the intravascular inflammatory pathway. For example, chronic inflammation is the main cause of age-related atherosclerosis, possibly exerting its effect through the IL-6 signaling pathway. Furthermore, inflammatory factors released by senescent cells result in a senescence-associated secretory phenotype and even atherosclerosis. Selective targeting and elimination of these senescent cells has been shown to slow the growth of atherosclerotic lesions by reducing the release of inflammatory and adhesion factors.

However, the potential mechanism by which inflamm-aging induces atherosclerosis needs to be studied more thoroughly, and there is currently a lack of powerful prediction models. Here, an improved inflamm-aging prediction model was constructed by integrating aging, inflammation, and disease markers with the help of machine learning methods; then, inflamm-aging scores were calculated. In addition, the causal relationship between aging and disease was identified using Mendelian randomization. A series of risk factors were also identified by causal analysis, sensitivity analysis, and network analysis. Our results revealed an accelerated inflamm-aging pattern in atherosclerosis and suggested a causal relationship between inflamm-aging and atherosclerosis. Mechanisms involving inflammation, nutritional balance, vascular homeostasis, and oxidative stress were found to be driving factors of atherosclerosis in the context of inflamm-aging.

Link: https://doi.org/10.3389/fgene.2022.865827

For more than a decade, researchers have been turning out studies to show that more time spent sitting correlates with a greater risk of mortality. Today's research materials are a recent example of the type, the analysis carried out in a sizable study population. The most obvious cause to suggest is that people who spend more time sedentary also spend less time exercising, and it is the amount of exercise that actually matters. There are studies controlling for exercise level that show that sitting time correlates with mortality independently of exercise level, and there are studies that claim the opposite, that it is all about the degree of exercise rather than the time spent sitting. This is business as usual in the field of epidemiology; one can't take any one study at face value. On any question of this nature, a survey of a dozen or more studies is a good idea.

Why would greater time spent sitting raise the risk of mortality even in people who obtain the recommended level of exercise? One possible line of evidence to consider is the use of accelerometers in daily life to show that even light activity in older people, such as casual walking, gardening, and the like, is associated with reduced mortality. It is possible that more is always better, even given a normal exercise schedule. Further, work on establishing a dose-response curve for exercise has indicated that the presently recommended level of exercise is too low to be optimal. Which again might suggest that adding more, even light activity, could improve matters. Another way of looking at it is to consider whether altered metabolic states, both beneficial and harmful, may produce larger effects the longer that they are maintained. Thus lengthy immobility may produce a greater cost to health and shorter periods of immobility broken by up by light activity. Supporting any of these hypotheses with data is, of course, the challenge.

Association of Sitting Time With Mortality and Cardiovascular Events in High-Income, Middle-Income, and Low-Income Countries

This population-based cohort study included participants aged 35 to 70 years recruited from January 1, 2003, and followed up until August 31, 2021, in 21 high-income, middle-income, and low-income countries with a median follow-up of 11.1 years. Daily sitting time was measured using the International Physical Activity Questionnaire. The measured outcome was a composite of all-cause mortality and major cardiovascular disease (CVD), defined as cardiovascular death, myocardial infarction, stroke, or heart failure.

Of 105,677 participants, 61,925 (58.6%) were women, and the mean age was 50.4 years. During a median follow-up of 11.1 years, 6,233 deaths and 5,696 major cardiovascular events (2,349 myocardial infarctions, 2,966 strokes, 671 heart failure, and 1,792 cardiovascular deaths) were documented. Compared with the reference group (less then 4 hours per day of sitting), higher sitting time (more than 8 hours per day) was associated with an increased risk of the composite outcome (hazard ratio [HR] 1.19), all-cause mortality (HR 1.20), and major CVD (HR 1.21).

When stratified by country income levels, the association of sitting time with the composite outcome was stronger in low-income and lower-middle-income countries (≥8 hours per day: HR 1.29) compared with high-income and upper-middle-income countries (HR 1.08). Compared with those who reported sitting time less than 4 hours per day and high physical activity level, participants who sat for 8 or more hours per day experienced a 17% to 50% higher associated risk of the composite outcome across physical activity levels; and the risk was attenuated along with increased physical activity levels.

Atherosclerosis is a condition of localized excesses of cholesterol in blood vessel walls, leading to fatty plaques that narrow and weaken those vessels, ultimately leading to stroke or heart attack. A lot of attention is given to the way in which excess cholesterol induces dysfunction in the macrophage cells responsible for clearing that cholesterol from blood vessel walls, thereby creating a feedback loop in which atherosclerotic plaques grow. Researchers here instead look at the effects of excess cholesterol on smooth muscle cells, and how it draws them into making the problem worse.

"We are trying to identify new pathways that cause atherosclerotic plaque buildup, in particular pathways that involve a certain cell type, called smooth muscle cells. For many years, researchers have been focused on other cell types, like endothelial cells and macrophages, but more recent studies have highlighted a role of smooth muscle cells in plaque formation. We found that if we block a specific protein in smooth muscle cells, we can effectively block the majority of plaque formation from occurring in an animal model."

Using a knockout method, researchers fed genetically modified mice a high fat diet and caused the mice to have high cholesterol levels in their blood to drive atherosclerotic plaque formation. Blocking a specific protein called PERK in these mice resulted in an 80% decrease of atherosclerotic plaque buildup in male mice. "This tells us that blocking PERK in smooth muscle cells is important in plaque formation. Interestingly, this protein is activated in smooth muscle cells by too much cholesterol in the cells. There are a lot of drugs on the market that block the smooth muscle cell pathway. Now that we know this buildup can be blocked by targeting smooth muscle cells, we can use medication that is already available and target this pathway to help patients with atherosclerotic plaque buildup. This is just another way we can block or lower the plaque buildup, especially for those who are unable to prevent atherosclerosis with lifestyle modifications or statins."

Link: https://www.uth.edu/news/story/targeting-a-specific-protein-in-smooth-muscle-cells-may-dramatically-reduce-atherosclerotic-plaque-formation

Exercise helps to downregulate appetite, among its many other beneficial outcomes. Researchers here point to raised levels of N-lactoyl-phenylalanine as an important part of this connection, one of a family of compounds formed as a result of exercise. In the present environment of prevalent obesity, a sizable amount of research into the biochemistry of exercise is directed towards its effects on consumption of food.

"Regular exercise has been proven to help weight loss, regulate appetite, and improve the metabolic profile, especially for people who are overweight and obese. If we can understand the mechanism by which exercise triggers these benefits, then we are closer to helping many people improve their health. We wanted to understand how exercise works at the molecular level to be able to capture some of its benefits. For example, older or frail people who cannot exercise enough, may one day benefit from taking a medication that can help slow down osteoporosis, heart disease, or other conditions."

Researchers conducted comprehensive analyses of blood plasma compounds from mice following intense treadmill running. The most significantly induced molecule was a modified amino acid called N-lactoyl-phenylalanine (Lac-Phe). It is synthesized from lactate (a byproduct of strenuous exercise that is responsible for the burning sensation in muscles) and phenylalanine (an amino acid that is one of the building blocks of proteins). In mice with diet-induced obesity (fed a high-fat diet), a high dose of Lac-Phe suppressed food intake by about 50% compared to control mice over a period of 12 hours without affecting their movement or energy expenditure. When administered to the mice for 10 days, Lac-Phe reduced cumulative food intake and body weight (owing to loss of body fat) and improved glucose tolerance.

The researchers also identified an enzyme called CNDP2 that is involved in the production of Lac-Phe and showed that mice lacking this enzyme did not lose as much weight on an exercise regime as a control group on the same exercise plan. Interestingly, the team also found robust elevations in plasma Lac-Phe levels following physical activity in racehorses and humans. Data from a human exercise cohort showed that sprint exercise induced the most dramatic increase in plasma Lac-Phe, followed by resistance training and then endurance training.

Link: https://www.bcm.edu/news/the-benefits-of-exercise-in-a-pill-science-is-closer-to-that-goal

Both the innate and adaptive immune systems decline in function and run awry with age. Taken as a whole, researchers view this as the combination of inflammaging and immunosenescence. Without delving into the details, inflammaging is chronic, unresolved inflammatory signaling, an overactivation of the immune system that produces harmful changes in cell behavior throughout the body, while immunosenescence is a decline in the effectiveness of the immune response, leaving an individual more vulnerable to pathogens and potentially cancerous cells, while also allowing senescent cells to accumulate in tissues. The two broad categories of dysfunction interact in a number of ways. Rising numbers of senescent cells, resulting from faltering immune surveillance, contribute meaningfully to inflammaging via their pro-inflammatory signaling, for example.

The aging of the innate immune system is quite different from that of the adaptive immune system, and arguably a great deal more is known about how to effectively deal with the latter issue. Restoring proper T cell production, via regeneration of the thymus and the hematopoietic cell populations of the bone marrow, and clearing out dysfunctional T cell populations may solve a great deal of adaptive immune aging. The innate immune system, on the other hand, suffers more complex, less well explored issues in cell behavior, and is also provoked into inflammatory signaling by problems such as the DNA debris that characterizes the aged tissue environment, for which researchers as yet do not have good solutions, or even paths to solutions.

Given that, it is interesting to note studies such as this one, in which researchers note that aged innate immune cells seem to react as well as young innate immune cells to approaches such as trained immunity, essentially vaccination with specific compounds, that can improve function and suppress inflammation in conditions involved excessive inflammatory signaling, such as respiratory infection and sepsis.

Trained Immunity Enhances Human Monocyte Function in Aging and Sepsis

Over the past two decades there has been an increased incidence of sepsis and this trend is likely to continue due to our aging population, increased use of immunosuppressive drugs and invasive procedures, and the emergence of antibiotic resistant opportunistic pathogens. Age has emerged as an independent predictor of morbidity and mortality in sepsis. Indeed, 60% of sepsis cases occur in patients over 65 years of age. It is generally accepted that age related immune senescence increases susceptibility to infection and sepsis, which raises the question of whether it is possible to modulate the aging immune system to improve resistance to infection. One possible approach to enhancing immune function during aging is innate immune training.

There is a substantial literature demonstrating that the innate immune system can be trained to respond more rapidly and effectively to infection. This phenomenon is referred to as "trained immunity" or "innate immune memory". Trained immunity is characterized by metabolic and epigenetic reprogramming in leukocytes in conjunction with enhanced antimicrobial functions. However, there is very limited information available on the effect of trained immunity in aging and/or sepsis. In 2011, it was reported that BCG vaccination prevented respiratory infections and improved cytokine production in individuals 60-75 years of age. Additionally, a 2020 clinical trial found that BCG vaccination increased protection from infection in individuals over 65 years old. While trained immunity increases inflammatory cytokine production upon restiumulation, interestingly it was found that BCG vaccination reduces systemic inflammation. It is now known that BCG, a potent immune training agent, induces the immune trained phenotype in humans, thus it is reasonable to speculate that the effect of BCG on respiratory infections in aging subjects may be mediated, in part, by trained immunity.

In this study, we examined innate immune training in monocytes isolated from healthy aging subjects and compared and contrasted their response to immune training with monocytes isolated from younger healthy individuals. We also examined innate immune training in monocytes derived from patients diagnosed with sepsis. We found that trained immunity increases metabolism and functionality of monocytes isolated from healthy aging subjects as well as in sepsis patients. In conclusion, this study confirms that innate immune training can be induced in aging healthy individuals as well as critically ill sepsis patients. We found that innate immune training can be induced regardless of age and there was no substantive difference in the immune trained phenotype as a function of age. We employed β-glucan as our immune training stimulus. The ability of glucan to induce the trained phenotype suggests that it may be possible to pharmacologically induce the immune trained phenotype in aging human immunocytes.

Very little work takes place on combinations of interventions known to target mechanisms of aging. This is largely, I suspect, for reasons relating to intellectual property and control of later development. The work that does take place usually looks at approaches known or likely to have minimal effects in long-lived species such as our own, even while producing sizable gains in short-lived species, and this open access paper follows that trend.

It is unfortunate that short-lived species exhibit a pace of aging that is so much more reactive to the environment than that of long-lived species, as it has biased a great deal of research into directions, such as analysis of the beneficial response to calorie restriction, that cannot possibly greatly extend human life span. Nonetheless, researchers presently know next to nothing about how different approaches to slowing aging interact with one another. Can ten or twenty different marginal approaches be combined to form a more impressive outcome? No-one knows, but projects such as this one may help to set expectations.

In this study, we investigated whether the combined application of several interventions with potential anti-aging action causes a cumulative effect on lifespan extension in flies. As for anti-aging drugs, we used rapamycin, the well-known mTOR signaling inhibitor, and two plant-derived compounds, particularly, alkaloid berberine and carotenoid fucoxanthin, whose geroprotective properties have been studied on different biological models.

We studied the effects of dietary restriction and co-administration of berberine, fucoxanthin, and rapamycin in constant darkness and low-temperature conditions using the D. melanogaster model. In addition, to address whether the long-lived strain demonstrates an enhanced geroprotective effect of the interventions' combinations, we studied the long-lived Enhancer of zeste (E(z)) mutant flies.

In the current study, using a combination of several geroprotective interventions, we managed to more than double the lifespan of flies, which is significantly more than using each intervention separately. This is the first report on the increase of maximum flies' lifespan to more than 200 days (120% increase). This result is most likely associated with the synergistic effect of interventions that led to a global metabolic network reorganization and ultimately to beneficially affected lifespan through the modulation of several molecular signaling pathways at once.

Link: https://doi.org/10.1038/s42003-022-03524-4

The heart becomes larger and weaker in response to the raised blood pressure of hypertension, though inflammatory signaling clearly also plays an important role. Note the study that showed clearance of senescent cells, and thus removal of their pro-inflammatory signaling, reversed cardiac hypertrophy in mice. In the research noted here, scientists discuss the sensing mechanisms that link blood pressure with hypertrophy of the heart. Sabotaging that system is not as good as prevention of hypertension, as targeting deeper issues should always be better than preventing just a few of their consequences, but will no doubt give rise to the development of small molecule drugs regardless.

Despite advances in cardiovascular medicine over the last 30 years, pathological left ventricular (LV) hypertrophy (LVH) secondary to pressure overload resulting from hypertension or aortic stenosis remains a powerful independent predictor of cardiovascular mortality and morbidity. Thus far, the only treatment available for this condition is blood pressure reduction with anti-hypertensive medications or replacement of a stenotic aortic valve. These strategies do not fully reverse the pathological remodeling that occurs once LVH is established.

We have shown recently that the Ca2+-activated TRPM4 ion channel acts as a positive regulator of pressure overload-induced cardiac hypertrophy. Given that TRPM4 is not activated by membrane stretch, the question remains as to the identity of the molecule at the start of the hypertrophic signaling cascade that senses changes in mechanical load within the myocardium and transduces that mechanical signal into a chemical signal that activates TRPM4. A prime candidate to act upstream of TRPM4 within this mechanosensory signaling cascade that drives LVH is the Ca2+-permeable mechanosensitive ion channel, Piezo1. Despite the significant evidence for a key role of Piezo1 channels in vascular physiology and pathophysiology, little is known about the role of Piezo1 in cardiac biology.

Here we show that Piezo1, which is both stretch-activated and Ca2+-permeable, is the mechanosensor that transduces increased myocardial forces into the chemical signal that initiates hypertrophic signaling via a close physical interaction with TRPM4. Cardiomyocyte-specific deletion of Piezo1 in adult mice inhibited the hypertrophic response. Piezo1 deletion prevented upregulation of the sodium-calcium exchanger and changes in other Ca2+ handling proteins after pressure overload. These findings establish Piezo1 as the cardiomyocyte mechanosensor that instigates the maladaptive hypertrophic response to pressure overload, and as a potential therapeutic target.

Link: https://doi.org/10.1038/s44161-022-00082-0

Chronic inflammation is of great importance in age-related degeneration. In later life, inflammatory signaling becomes constant and unresolved, in contrast to the short-term, rapidly resolved inflammation that occurs in response to infection and injury in youth. This unresolved inflammation is highly disruptive of tissue function and structure. In response to unrelenting inflammatory signaling, cell behaviors change in pathological ways, such as the deposition of calcium into blood vessel walls, or increasing quiescence of stem cells that should be actively supporting tissue.

Researchers are in search of ways to suppress the excessive inflammation of aging, but so far the only compelling approaches involve removing the causes of inflammatory signaling, such as the growing population of senescent cells. Otherwise interfering in any specific inflammatory signal via the usual means, removing proteins, blocking receptors, and so forth, means suppressing both excessive and appropriate inflammation. It is certainly possible that some signaling is largely only involved in the excessive inflammation of aging, but to date it appears that any effective mechanism to be targeted in the reduction of chronic inflammation is likely also needed in the normal defense against pathogens and potentially cancerous cells.

A greater focus on the causes of chronic inflammation is needed. Beyond senescent cells, the age-damaged environment generates DNA debris, for example, that triggers the innate immune system in the same ways as infection and injury. It is unclear as to what the best solution to clearing this debris might be, but success here is likely to produce greater benefits with fewer side-effects than the search for novel portions of the complex mechanisms of inflammatory signaling that can be blocked to suppress inflammation.

CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure

Pathological cardiac remodeling, characterized by left ventricular (LV) hypertrophy, cardiac fibrosis, and inflammation, is a determinant of the clinical course of heart failure (HF). Aging and the activation of the rennin-angiotensin system play an important role in pathological cardiac remodeling. Anti-aging treatments, such as caloric restriction and rennin-angiotensin system-inhibitor use, potentially improve HF by reducing cardiac inflammation. Evidence corroborating the potential benefit of inflammation suppression in reducing cardiovascular disease is increasing. For example, canakinumab, a therapeutic human monoclonal antibody targeting IL-1β, has been shown to significantly lower major adverse cardiovascular event rates. However, the effectiveness of anti-inflammatory therapy in HF awaits full elucidation.

Chemokines and chemokine receptors are important components of the cytokines that orchestrate immune-cell migration and maintain homeostasis. Early research has established that C-C motif chemokine ligand 17 (CCL17) plays an important role in T cell development in the thymus, and it binds to C-C chemokine receptor 4 (CCR4). We have demonstrated that chemokine CCL17, an important regulator of atherosclerosis, is positively associated with coronary artery disease, independent of traditional cardiovascular risk factors. Chemokines are currently believed to be involved in all stages of cardiovascular response to injury and are considered a possible therapeutic target. However, the role of CCL17 in pathological cardiac hypertrophy is yet to be investigated.

Given the current lack of age-related molecules for HF treatment, the elucidation of underlying molecular mechanisms and discovery of potential targets through the combination of clinical cohorts and aging-disease models are warranted. Herein, we report CCL17's tendency to display an age-dependent increase in population studies and potential role as a critical participant in age-related and angiotensin II (Ang II)-induced cardiac hypertrophy and HF. Subsequent animal experiments further revealed that Ccl17 knockout significantly repressed aging and angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis, accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II-induced pathological cardiac remodeling in mice. Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related and Ang II-induced pathological cardiac hypertrophy and heart failure.

There are likely many processes and components involved in cellular maintenance that remain poorly explored, with the work here on BAG2 condensates serving as an example of the type. Cells work to remove damage, and many lines of evidence show that enhancing that outcome improves cell and tissue function, slowing aging. Much of this work emerges from the study of calorie restriction as a means to extend life in short-lived species, but that is just one slice of a much broader area of research. It remains an open question as to whether any of this will lead to effective ways to slow aging in humans, however, given that ways to enhance, say, the processes of autophagy have so far proven disappointing in humans, failing to improve significantly upon the effects of exercise or a lowered calorie intake.

Biomolecular condensates are organelles that don't have the recognizable cell membrane enclosure, but instead, are separated from the surrounding cytoplasm by a difference in density that can be loosely compared to a drop of oil in water. This liquid-liquid phase separation creates a specialized, relatively concentrated environment for certain functions and reactions. For example, a stress granule is a membraneless organelle that appears when the cell is under stress - maybe there's too much glucose, maybe it's too hot or cold, maybe the cell is experiencing dehydration - and its job is to sweep up RNA floating around in the cytoplasm, storing those genetic instructions and pausing their translation into proteins.

"When there's stress, what happens to the proteins that are already in the cell? If they're under those stress conditions, some of those proteins could get damaged and they could misfold." Misfolds of the tau protein, for example, can become pathological and turn into the neurofibrillary tangles that characterize Alzheimer's disease. This is where the newly discovered BAG2 condensate comes in. Named for the BAG2 protein that it contains, the organelle is capable of sweeping up these faulty proteins in the cytoplasm and stuffing them into a proteasome - the cell's version of a trash can - located in the organelle. This inactivates and breaks down the protein. Many proteasomes are present in cells at any given time, he added, but what makes this particular proteasome (labeled 20S) special is that it can accept proteins that are already somewhat misfolded and would not fit in the other cellular trash cans.

Additionally, this method of protein degradation does not rely on the ubiquitination process, in which proteins meant for destruction are marked with a tiny ubiquitin protein tag before being grabbed by the proteasome. The role of the BAG2 protein in this context is not yet fully defined, but researchers suspects that it may have a role in helping organize the messy protein before it goes into the 20S proteasome. "What these BAG2 condensates seem to do, at least in the case of tau, is they can actually travel to the damaged tau and gobble it up. The BAG2 condensate really is an ideal place for damaged tau. It would be really nice to figure out how we can shuttle tau into this condensate at the early stages of its damage for the cell to get rid of it, before it gets worse."

Link: https://www.eurekalert.org/news-releases/955889

Sustained psychological stress is well known to correlate with poor health and accelerated manifestations of aging, when looking at the epidemiology of sizable study populations. Here, researchers link stress to the age-related decline of the immune system, an important aspect of aging that affects tissue function throughout the body. It is tempting to point to inflammatory signaling as the mechanism of importance, but the conclusion here is that the effects of stress on health are in large part mediated by poor lifestyle choices, such as a worse diet and less exercise, that in turn produce a worse metabolism and more rapid degenerative aging.

To measure exposure to various types of social stress, the researchers analyzed responses from a national sample of 5,744 adults over the age of 50. They answered a questionnaire designed to assess respondents' experiences with social stress, including stressful life events, chronic stress, everyday discrimination, and lifetime discrimination. Blood samples from the participants were then analyzed through flow cytometry, a lab technique that counts and classifies blood cells as they pass one-by-one in a narrow stream in front of a laser.

As expected, people with higher stress scores had older-seeming immune profiles, with lower percentages of fresh disease fighters and higher percentages of worn-out white blood cells. The association between stressful life events and fewer ready-to-respond, naive T cells remained strong even after controlling for education, smoking, drinking, BMI, and race or ethnicity.

Some sources of stress may be impossible to control, but the researchers say there may be a workaround. T-cells - a critical component of immunity - mature in a gland called the thymus, which sits just in front of and above the heart. As people age, the tissue in their thymus shrinks and is replaced by fatty tissue, resulting in reduced production of immune cells. Past research suggests that this process is accelerated by lifestyle factors like poor diet and low exercise, which are both associated with social stress. "In this study, after statistically controlling for poor diet and low exercise, the connection between stress and accelerated immune aging wasn't as strong. What this means is people who experience more stress tend to have poorer diet and exercise habits, partly explaining why they have more accelerated immune aging."

Link: https://news.usc.edu/200213/stress-aging-immune-system/

Calcification in arteries is an age-related malfunction of cell behavior, in which cells in blood vessel walls inappropriately take on some of the behaviors of bone cells called osteoblasts. These errant cells deposit calcium structures characteristic of bone tissue into the extracellular matrix, and that is in turn disruptive of tissue properties, particularly to the elasticity needed for constriction and dilation of blood vessels. In effect, blood vessels, and other structures such as heart valves that are subject to calcification, are slowly turning into bone. This causes cardiovascular dysfunctions that, given time, will ultimately prove fatal.

As noted in today's open access review paper, calcification proceeds side by side with the development of atherosclerosis, the formation of fatty deposits in blood vessel walls that narrow and weaken blood vessels. These are two quite distinct processes, however. That they do coincide is most likely because both are influenced strongly by the state of inflammatory signaling, in the body at large, and localized to particular regions of blood vessel walls. Atherosclerosis produces inflamed areas of the blood vessel wall, where lesions form, by virtue of the way in which it derives from and interacts with the malfunction and inflammatory signaling of macrophage cells of the innate immune system. The surrounding vessel is thus more prone to calcification.

Arterial Calcification and Its Association With Stroke: Implication of Risk, Prognosis, Treatment Response, and Prevention

Vascular calcification (VC) is one of the characteristics of vascular aging and appears to specifically occur in arteries. It is defined as the deposition of calcium-phosphate complexes in the vessels. Apart from aging, pathological processes like diabetes mellitus, chronic kidney disease, and hereditary disorders might also be the risk factors for arterial calcification. Calcification at different locations in the arterial wall might be associated with different risk factors and outcomes. Intimal calcification is closely related to atherosclerosis and affects the stability of the plaque, while medial calcification, including calcification located in the tunica media and around the internal elastic lamina, is considered to cause arterial stiffening and reduce compliance.

Arterial calcification can take place in various vessels, such as the femoral artery, abdominal aorta, thoracic aorta, coronary artery, carotid artery, and cerebral arteries. Among these, the best-studied are coronary artery calcification (CAC), intracranial artery calcification (IAC), and carotid artery calcification. CAC has been used as a predictor of coronary heart disease and recent studies have shown that CAC can also predict the risk of atherosclerotic cardiovascular disease, including stroke. Similarly, IAC, especially intracranial internal carotid artery calcification (IICAC), and carotid artery calcification are also reported to be closely associated with stroke.

Arterial calcification including IAC, CAC, and carotid calcification can predict the risk of stroke and it also affects treatment response and prognosis of stroke patients. Arterial calcifications and stroke share many risk factors, and in fact, history of ischemic stroke is one of the risk factors for IAC. Arterial calcification might affect plaque stability or cause hemodynamic changes, and therefore increase the risk of stroke. Besides, IAC or CAC indicates atherosclerosis, which is one of the main causes of stroke. It is worth noting that besides the total amount of calcification, the morphology, distribution, and size (large or small) of calcification can also impact on the risk of stroke. Intimal calcification and medial calcification have distinct implications and should be studied separately.

Elastin in the extracellular matrix is important in determining the elasticity of tissue. That elasticity is lost with age, as elastin structure changes in detrimental ways. Because the structure of elastin in tissue is complex, and largely only laid down during development, it seems likely that the best path towards repairing it in old tissues is some form of coercing or reprogramming cells to maintain the elastin structure as they did during the developmental portion of life. As yet, few approaches have made any meaningful inroads in this direction. A few small molecules like minoxidil appear to provoke elastin deposition to some degree, while the biotech company Elastrin is working on a way to remove damaged elastin molecules. This is an important topic, as loss of elasticity in blood vessels is a contributing factor in cardiovascular disease, but as yet is not receiving sufficient attention.

Aging-related degeneration of elastic fibres causes skin wrinkles and loss of elasticity. A correlation has been reported between dermal elastic fibre degradation and wrinkles. However, the mechanism of wrinkle formation is complex and unclear. To establish methods for treating wrinkles, it is necessary to understand the aging-related morphological alterations underlying elastin fibre degradation or disappearance. Recently, three-dimensional (3D) imaging combined with decolourization and fluorescent immunostaining has been used to facilitate the visualization of several tissues, organs, and whole mice. In this study, we aimed to apply the decolourization technique to excised human skin tissue and to observe the 3D structure of elastin fibres. Moreover, to evaluate the elastin fibre structure objectively and quantitatively, we established a computational 3D structural analysis method for 3D imaging.

The 3D observations of the inner skin structures revealed that the structures in the abdominal and eyelid tissues were fundamentally different. In the abdominal skin, oxytalan fibres, which are rich in fibrillin-1, exhibiting a candelabra-like structure, were observed just below the basement membrane, as previously reported. However, in the eyelid skin, a complex entangled network of elastin fibres was observed below the basement membrane, which did not show the candelabra-like structure. The image observation and analysis indicated that the proportion of fibrillin-1 in the eyelid skin was higher than that in the abdomen skin. Although it was unclear whether these differences were due to congenital differences during tissue development or acquired differences due to ultraviolet rays and mechanical movements, it was interesting to understand the mechanism of elastin fibre formation.

In the aged skin from the eyelid and abdomen, the elastin fibres had a short, shrunk and spherical shape compared to the young skin. Because these alterations were common in the eyelid and abdominal skin, they might be because of the intrinsic and chronic physiological process of aging, ischemia, and inflammation and might not depend on characteristic differences, such as on the effects of ultraviolet (UV) irradiation or mechanical irritation, between body parts. In contrast, although these altered parameters were common in the eyelid and abdominal skin, the degree of alteration with age was more significant in the eyelid skin. In addition, the number of fibre branches decreased with aging in the eyelid skin but not in the abdominal skin. It has been reported that the fibrous structure of the skin is associated with wrinkle formation and skin elasticity.

Truncation of fibrillin-rich microfibrils in photo-exposed skin, visualized in 2D, has been reported. The 3D observation and computational analysis performed in this study further support the previous data. Elastin-degrading enzymes, UV-induced reactive oxygen species and frequent mechanical movements might cause these changes in elastin fibres in the eyelid skin. Alternatively, it might also be due to the differences in basic fibre properties, such as the elastin fibre network in the eyelid and the high content of fibrillin-1, as mentioned above.

Link: https://doi.org/10.1002/ski2.58

TDP-43 is one of the proteins more recently discovered to become phosphorylated and form harmful aggregates in aged tissues. These aggregates are connected to a range of neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS). Researchers here discuss a novel way to use TDP-43 as a biomarker for the early onset of ALS. Being able to quantify the progression of neurodegenerative conditions in their early stages is a necessary part of the development of effective means of prevention.

Clinicians diagnose ALS based on deteriorating motor function, such as weakness in the arms or legs or difficulty walking. Motor neurons in the brain and spinal cord of people with ALS contain cytoplasmic inclusions of TDP-43, but currently, these can only be detected after a person has died. Recently, other researchers had looked for TDP-43 in muscle biopsies from three cases, spotting inclusions within intramuscular nerve bundles.

To see if this held true in a larger sample, researchers analyzed bicep, quadricep, diaphragm, or tongue muscles postmortem from 10 sporadic ALS cases and 12 age- and sex-matched controls. Within the tissue, they saw intramuscular nerves that had atrophied and puncta of phosphorylated TDP-43 in nerve axons. Neither occurred in the control tissue. Hyperphosphorylated TDP-43 forms aggregates in ALS and other neurodegenerative diseases. The findings suggest that TDP-43 inclusions within muscle tissue could become a marker for late-stage ALS.

What about early stage disease? Researchers analyzed muscle biopsies taken from adults who were experiencing muscle weakness. Of the available biopsies from 114 participants, 71 had captured intramuscular nerve bundles. Of these samples, 33 contained TDP-43 inclusions in nerve axons. All 33 volunteers were subsequently diagnosed with ALS an average of five months after biopsy. Of the 38 participants whose biopsies contained nerve bundles but no TDP-43 inclusions, none developed ALS; rather, all were later diagnosed with a different neurodegenerative disease, such as spinal muscular atrophy.

Link: https://www.alzforum.org/news/research-news/aggregates-tdp-43-muscle-potential-als-marker

Parabiosis studies involve connecting the circulatory systems of two genetically identical mice, resulting in modest rejuvenation in the older mouse of the pair. The path from those animal studies to age-modifying therapies in humans has been one of twists and turns. At first, the research community focused on potentially beneficial factors in young blood. Elevian's work on GDF11 is still ongoing as an outcome of that research. Over the same period of time, plasma transfusions from young to old humans have produced a lack of convincing data.

Later experiments strongly suggested that the real benefit was dilution of harmful factors in old blood, and it remains to be seen as to where that leaves Elevian. Of late, further evidence has arisen to point to the quality of albumin in blood as an important factor, with the hypothesis that dilution works because it usually involves delivery of albumin along with saline or plasma, and thus reduces the amount of harmfully modified albumin already in circulation, rather than for any other reason. Dilution is fairly easy to carry out, and physicians are already doing this for self-experimenters. It still needs a reasonably sized human trial, however, to confirm the beneficial results observed in animal studies.

Lfyspn is a new company set up to run exactly this sort of clinical trial, to establish plasma dilution, or albumin replacement, or both, as simple means to improve late life health. Their view is that this is an approach that should be considered immunomodulatory in nature, leading to a reduction in inflammatory signaling and improvements in tissue function downstream of that primary effect. More research is needed in order to understand the details, but benefits to health in humans can still be quantified well in advance of that work.

A new clinical trial is hoping to move the needle on therapeutic plasma exchange - and is looking for participants

Plasmapheresis is a procedure that removes plasma from whole blood, swapping out unhealthy plasma and replacing it with healthy donor plasma or a plasma substitute. Plasma is part of blood, a fluid made up of water, proteins, and essential nutrients. In certain diseases, as well as in aging individuals, certain harmful substances accumulate in plasma and may lead to organ damage. Lyfspn, a company backed by Khosla Ventures, is conducting a plasmapheresis trial in the Bay Area for longevity benefits - and is actively seeking trial participants, particularly those from the biohacking community.

The idea that plasmapheresis could aid longevity started, as is so often the case, in mice, in an experiment called parabiosis. It was shown that when two mice - one old, one young - are connected through their skin, the end result is common circulation, with the blood of each animal, in effect, diluted by 50% and the young mouse experiencing accelerated aging and the older mouse benefiting from rejuvenation. Experiments over the last seven or eight years to discover exactly what it is in the blood that causes this rejuvenation have failed at a cost of millions of dollars. A change of approach was needed. "Last year we published other experiments in mice, that didn't involve connecting two mice. Instead, we transfused blood from mice into another - a process we call dilution - and we saw the same beneficial effects occurring."

"What else became obvious from the original research is that the effect isn't just the removal of bad substances from the blood. This is something people don't pay close attention to, but plasmapheresis, probably by the removal of certain substances, actually causes immunomodulation - the whole immune system functions differently, and, for the most part it functions better after plasmapheresis, with an increase in certain beneficial factors in the blood. This is one of the most exciting findings, but it's a complex process that warrants this further research."

Lyfspn

Lyfspn is a physician-led venture-backed startup company working to invent novel therapies that will allow us live longer, healthier lives. The Lyfspn team is passionate about bringing therapies to the world that find their basis in basic science research. Lyfspn is currently planning to carry out a pilot study of our lead longevity promoting therapy candidate, a novel apheresis-based treatment. Apheresis is an existing therapeutic modality which plays an important role in the management of many diseases including more than 50 autoimmune disorders, a number of rare neurologic conditions, and Alzheimer's disease. Apheresis is emerging as a prevention and therapy for other age related medical conditions.

Previous studies have shown benefits in some mouse models of Alzheimer's disease (not the one chosen here) via clearance of senescent cells. These cells produce chronic inflammation, and that inflammation is thought to be influential in driving the pathology of Alzheimer's disease. One caveat is that these models are highly artificial, but nonetheless, there is good evidence for the human condition to involve cellular senescence and otherwise inflammatory behavior in the supporting cells of the brain.

Researchers here note that USP16 inhibition improves function in an Alzheimer's mouse model; this acts to downregulate Cdkn2a, one of the gene loci involved in the onset of cellular senescence. The results here are supportive of a role for cellular senescence in neurodegeneration, but suppression of the onset of cellular senescence may or may not be the best approach. Where inflammation is driving undamaged cells into senescence, then it could be beneficial. But there is always the risk of suppressing senescence for cells that really should become senescent, to protect against potentially cancerous damage. Where the balance of benefit and risk falls can only really be determined by experiment.

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease.

We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.

Link: https://doi.org/10.7554/eLife.66037

Reseachers here demonstrate that engineering the mesenchymal stem cells provided in a cell therapy to overexpress HIF1α produces regeneration in a pig model of heart failure. The mechanisms involved are up for debate, as they may or may not involve an extension of survival of the stem cells following transplant, versus a shift in cell signaling. Mesenchymal stem cells do not survive long in most such treatments, and their beneficial effects are the result of signals secreted in the short time they are present in tissues. Given the feasibility of engineering cells in vitro in any number of ways, this is a logical next step for the industry, now that first generation cell therapies are so well established.

Recent preclinical investigations and clinical trials with stem cells mostly studied bone-marrow-derived mononuclear cells (BM-MNCs), which so far failed to meet clinically significant functional study endpoints. BM-MNCs containing small proportions of stem cells provide little regenerative potential, while mesenchymal stem cells (MSCs) promise effective therapy via paracrine impact. Genetic engineering for rationally enhancing paracrine effects of implanted stem cells is an attractive option for further development of therapeutic cardiac repair strategies. Non-viral, efficient transfection methods promise improved clinical translation, longevity and a high level of gene delivery.

Hypoxia-induced factor 1α (HIF1α) is responsible for pro-angiogenic, anti-apoptotic and anti-remodeling mechanisms. Here we aimed to apply a cellular gene therapy model in chronic ischemic heart failure in pigs. A non-viral circular minicircle DNA vector was used for in vitro transfection of porcine MSCs (pMSC) with HIF1α (pMSC-MiCi-HIF-1α). pMSCs-MiCi-HIF-1α were injected endomyocardially into the border zone of an anterior myocardial infarction one month post-reperfused-infarct.

Animals underwent treatment one month after infarction, which more aptly reflects realistic clinical application, but arguably complicates successful outcomes, because the initial repair and immunological processes start immediately at the onset of infarction. Nonetheless, pMSC-MiCi-HIF-1α significantly reduced myocardial scar size and improved cardiac output. Our results thus underline the potential as a therapeutic concept.

Link: https://doi.org/10.3389/fbioe.2022.767985

The gut microbiome produces a broad range of necessary, beneficial metabolites, but the effects of only a few are well understood. Butyrate is one of the better studied of these metabolites, particularly in the context of cognitive function. Butyrate encourages BDNF expression, which in turn upregulates neurogenesis. Butyrate also upregulates expression of FGF21, which adjusts metabolism in ways that mimic some of the beneficial effects of calorie restriction. Unfortunately, shifts in the balance of populations in the gut microbiome take place with age, and butyrate production decreases as a result.

The innate immune cells called macrophages adopt packages of behaviors known as polarizations in response to circumstances. In today's open access paper, researchers note that butyrate adjusts the polarization of macrophage cells, from the pro-inflammatory M1 polarization to the anti-inflammatory, pro-regenerative M2 polarization. This is generally advantageous in the context of aged, inflamed tissue that tends towards fibrosis. Fibrosis is a malfunction of normal tissue maintenance that leads to scar-like deposition of collagen extracellular matrix, degrading tissue function. Organs such as the heart and kidney suffer fibrosis in later life, and there is presently little that can be done about that after the fact. A number of lines of work have shown that adjusting macrophage polarization towards M2, to dampen inflammation, can be beneficial in fibrotic tissues, however, and hence the interest here in the effects of butyrate on these cells.

Butyric Acid Ameliorates Myocardial Fibrosis by Regulating M1/M2 Polarization of Macrophages and Promoting Recovery of Mitochondrial Function

Myocardial fibrosis (MF) refers to various quantitative and qualitative changes in the myocardial interstitial collagen network. It is mainly manifested by the proliferation of myocardial fibroblasts, which secretes extracellular matrix proteins to replace damaged tissues. It is a common pathological manifestation in the end stage of many cardiovascular diseases and is the result of imbalance of collagen synthesis and metabolism. When MF occurs, it will damage the myocardial structure and promote arrhythmia and ischemia, thus affecting the evolution and outcome of heart disease.

Recent studies have shown that gut microbiota has a variety of effects on the host. Indeed, the functions of gut microbiota like an endocrine organ, producing bioactive metabolites that affect the physiological function of the host. There is growing awareness of the importance of the gut in many cardiovascular health and diseases, of which the role of the "gut-heart" axis is particularly important. Butyric acid is a short-chain fatty acid (SCFA) from the microbial community that involves in a series of cellular processes in a concentration-dependent manner. It is a multifunctional molecule produced by the fermentation of dietary fiber in the intestinal tract of mammals.

Macrophages are key cells in the immune inflammatory response. Activated macrophages are generally differentiated into M1 and M2 phenotypes. In addition to playing a role in host defense, macrophages also ensure tissue homeostasis and inhibit inflammatory responses. In order to perform these seemingly opposite functions, macrophages show high plasticity and adopt a spectrum of polarized states, where M1 macrophages and M2 macrophages are extreme. Both M1 macrophages and M2 macrophages are closely related to the inflammatory response, among which M1 macrophages are mainly involved in the pro-inflammatory response, and M2 macrophages are mainly involved in the anti-inflammatory response. Functionally, M2 macrophages inhibit M1-driven inflammation and promote tissue repair.

We hypothesized that M1-related mitochondrial oxidative phosphorylation inhibition is the factor that prevents M1 from repolarization to M2. Increasing the plasma concentration of butyric acid helps to protect the mitochondria, thereby repolarizing M2 from M1 to inhibit the progression of MF. To this end, we constructed a rat model of MF and fed rats with butyric acid. Our results suggested that butyric acid ameliorated MF by regulating M1/M2 polarization of macrophages and promoting recovery of mitochondrial function.

Researchers are beginning to apply epigenetic clocks to known cases in which drug treatment is associated with a longer life expectancy, even less unusual ones, such as this case. Patients treated with the antipsychotic drug clozapine exhibit a longer life expectancy, and epigenetic clock data now shows that male patients in addition experience a lowered epigenetic age. Whether any of this data proves useful at the end of the day is an open question. The challenge in the use of epigenetic clocks is that researchers don't yet understand how specific epigenetic marks connect to the underlying mechanisms of aging. Therefore clocks become unreliable in the context of interventions that address a given mechanism of aging: the clock may be biased towards or against that mechanism, and without calibrating the therapy against the clock in life span studies, it is impossible to draw conclusions from the data.

Long-term studies have shown significantly lower mortality rates in patients with continuous clozapine (CLZ) treatment than other antipsychotics. We aimed to evaluate epigenetic age and DNA methylome differences between CLZ-treated patients and those without psychopharmacological treatment. The DNA methylome was analyzed in 31 CLZ-treated patients with psychotic disorders and 56 patients with psychiatric disorders naive to psychopharmacological treatment. Delta age (Δage) was calculated as the difference between predicted epigenetic age and chronological age. CLZ-treated patients were stratified by sex, age, and years of treatment. Differential methylation sites between both groups were determined using linear regression models.

The Δage in CLZ-treated patients was on average lower compared with drug-naive patients for the three clocks analyzed; however, after data-stratification, this difference remained only in male patients. Additional differences were observed in Hannum and Horvath clocks when comparing chronological age and years of CLZ treatment. We identified 44,716 differentially methylated sites, of which 87.7% were hypomethylated in CLZ-treated patients, and enriched in the longevity pathway genes. Moreover, by protein-protein interaction, AMPK and insulin signaling pathways were found enriched. CLZ could promote a lower Δage in individuals with long-term treatment and modify the DNA methylome of the longevity-regulating pathways genes.

Link: https://doi.org/10.3389/fpsyt.2022.870656

Researchers are working towards the ability to regenerate the dental pulp inside teeth. Full regeneration of teeth has seemed perpetually on the verge of success for a decade or so now; it has been achieved as a proof of concept in rats, for example. Restoration of dental pulp is a more viable, less complex project, given the present state of research into the use of scaffolds to provoke regrowth.

Researchers have proposed an alternative to root canals in dentistry: restoring the lost tissue in the tooth cavity by inducing the body to regenerate it. Their goal is to develop a materials-based therapy that does not contain live cells and therefore could be sold off-the-shelf. It would be the first of its kind. The team has created an injectable hydrogel designed to recruit a person's own dental pulp stem cells directly to the disinfected cavity after a root canal. Composed of biocompatible peptides that aggregate into fibers, the hydrogel delivers biological cues to direct tissue growth, as well as a scaffold structure to support it.

A procedure known as over-instrumentation is performed on children's immature permanent teeth with necrotic pulp, prompting new growth of the still-forming root by eliciting a healing response. The tissue outside of the emptied canal, when poked, forms blood clots that secrete a growth factor that signals cells to produce new tissue to support the root. While some regrows, it is disorganized, lacks the needed tissue differentiation - including nerve cells - and fails to mimic soft tissue. By contrast, the team's hydrogel therapy mimics the body's own growth factor signaling, and, coupled with known antimicrobial mechanisms engineered into those materials, is capable of promoting tissue healing and regeneration.

In early animal studies, dogs injected with the team's hydrogels formed soft tissue from the tooth apex to the crown in just under a month. "We saw a lot of different tissues, including blood vessels, nerve bundles and pulp-like cells. One of the primary goals of this project is to determine the type of cells that reorganize and repopulate the regenerated tissue." One of the core challenges tissue engineers face is creating blood vasculature, the plumbing that delivers nutrients to regenerated cells. To address the problem, the team's hydrogel contains a protein known as vascular endothelial growth factor that stimulates the growth of new blood vessels.

Link: https://news.njit.edu/njit-led-team-revitalizes-teeth-through-tissue-regeneration

Inflammaging is the name given to the decline of the aging immune system into a state of constant, unresolved inflammation. Inflammatory signaling in the aged body arises in part because of an increased burden of senescent cells. These cells secrete a potent mix of pro-inflammatory signals, disrupting tissue function. This is one of the reasons why removal of lingering senescent cells produces such rapid rejuvenation, as these errant cells actively maintain a portion of the degradation of function and environment in aged tissues. Beyond senescent cells, the broad molecular damage and cellular dysfunction of aging produces circulating DNA debris, and similar outcomes, that are recognized by the innate immune system as indicative of infection or injury, leading to inflammatory behavior.

Beyond the removal of senescent cells, current approaches to suppression of inflammation, largely developed as treatments for autoimmune conditions, are crude and have significant long-term side-effects. Because they rely on suppression of specific signal molecules or their recognition, they inhibit not only excessive and inappropriate unresolved inflammation, but also the necessary short-term inflammation that is needed for regeneration, defense against pathogens, and elimination of damaged and potentially cancerous cells. More sophisticated approaches are needed, but given the overlap in signals and signal transduction between desirable and undesirable inflammation, it is unclear that anything will work really well other than removing the triggers that cause unresolved inflammation, as illustrated by the dramatic benefits observed in animal models following the removal of senescent cells.

Modern Concepts in Cardiovascular Disease: Inflamm-Aging

Under physiological conditions, inflammation protects against external pathogens and intrinsic degenerative processes. Nevertheless, dysregulation of the immune system, as seen during aging, triggers a persistent state of low-grade inflammation, which has been recognized as an important driver for the development of age-related diseases. This phenomenon, referred to as inflamm-aging, has been linked to a higher risk of cardiovascular (CV) events and has been increasingly recognized as a determinant of CV outcomes. Since CV disorders are the leading cause of death in industrialized countries, improving the treatment of these diseases implies prolonging the average lifespan. Furthermore, acute CV events, particularly stroke, are associated with long-term disability, inevitably resulting in a worsening of quality of life. Long-term disability, dependence on daily living, and reduced quality of life are the most relevant backlashes of aging; thus, addressing those aspects is pivotal in promoting healthy aging. Finally, inflamm-aging is also involved in other age-related disorders, like sarcopenia, cancer, and neurocognitive impairment, all having a heavy impact on lifespan and quality of life of elderly people. Therefore, targeting inflamm-aging may prolong lifespan and promote successful aging by acting on multiple levels.

Inflamm-aging was firstly theorized in the 2000s as a phenomenon involved in the age-related deterioration of physiological processes. Defined as a chronic low-grade sterile inflammation, inflamm-aging was suggested to result from persistent antigenic load and stress. Since then, this concept has been intensively studied to identify its molecular mechanisms and how it contributes to age-dependent diseases. Even though the exact mechanisms of inflamm-aging are not yet fully elucidated, some pathologic features have been identified.

Inflamm-aging develops due to senescent cell accumulation, altered function of immune cells, and increased inflammasome activity due to incremented levels of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). To date, wide experimental evidence validated the importance of inflamm-aging in the pathophysiology of CV diseases and the potential of targeting inflammation as pharmacological therapy. Nevertheless, none of the tested anti-inflammatory agents has yet been implemented in everyday clinical cardiology; thus, more work remains to be done to optimize these promising interventions. Ultimately, future studies are encouraged to discover further potential therapeutic targets involved in the complex mechanism of inflamm-aging. Along with other treatment strategies against different age-related alterations in molecular pathways, inflamm-aging targeted approaches will intently endure the burden of CV disease in the growing aging population.

This fascinating paper discusses the phenomenon of DNA gaps, essentially a double strand break in which the break is hidden from the usual mechanisms that respond to and repair such damage. The authors present evidence for these DNA gaps to be protective against DNA damage, noting that a loss of DNA gaps is associated with degenerative aging in animal models, both induced aging and natural aging. It is a little early to speculate on what can be done with this information, but it is interesting to join the dots with other research into DNA damage conducted in recent years.

The endogenous DNA damage triggering an aging progression in the elderly is prevented in youth, probably by naturally occurring DNA gaps. Decreased DNA gaps are found during chronological aging in yeast. So we named the gaps "Youth-DNA-GAPs." The gaps are hidden by histone deacetylation to prevent DNA break response and were also reduced in cells lacking either the high-mobility group box (HMGB) or the NAD-dependent histone deacetylase, SIR2. A reduction in DNA gaps results in shearing DNA strands and decreasing cell viability. The number of Youth-DNA-GAPs were low in senescent cells, two aging rat models, and the elderly. HMGB1 acts as molecular scissors in producing DNA gaps. Increased gaps consolidated DNA durability, leading to DNA protection and improved aging features in senescent cells and two aging rat models similar to those of young organisms.

Similar to other DNA modifications such as 5-methylcytosine that can be either epigenetic marks or DNA damage, both pathological DNA breaks and physiological DNA gaps are DNA modifications with the same DNA structure; however, pathological DNA breaks are DNA damage, and the physiological DNA gaps are epigenetic marks. By evaluating the correlation between Youth-DNA-GAPs and age, we concluded that Youth-DNA-GAPs are a ubiquitous DNA change existing in a wide range of eukaryotic cells, including yeast, rodents, and humans. Additionally, the reduction of Youth-DNA-GAPs varies based on the aging degree and this decrease can result from chemical-induced or natural aging. The reduction of Youth-DNA-GAPs was associated with aging phenotypes regardless of cause. In rats, decreased DNA gaps were found in both natural and D-gal-induced aging groups.

In yeast, a strong correlation was observed between the reduction in Youth-DNA-GAPs and viability in aging yeast cells. So the gap reduction is rather a marker of biological than chronological aging. This study showed a negative relationship between the gaps and the number of senescence cells. Moreover, we found a similar reduction in 30-month-old naturally and 7-month-old D-gal-induced aging rats. Given these consistent data from different eukaryotic organisms, it suggests that the Youth-DNA-GAP is a marker of phenotype-related aging degree

Link: https://doi.org/10.1096/fba.2021-00131

Neurogenesis, the creation of new neurons and subsequent integration into neural circuits, is necessary for maintenance and function of the brain, particularly in connection to memory. Unfortunately, neurogenesis declines with age. Here, researchers add to the existing body of evidence for chronic inflammation in the brain to contribute to this decline. Unresolved inflammation is considered to contribute to neurodegeneration in general, not just loss of neurogenesis. Finding ways to safely suppress excessive inflammation in the aging body and brain is a high priority in the treatment of aging as a medical condition.

Using brain tissues from non-human primates (NHPs), the ideal model to mimic human hippocampal aging, scientists have established the first single-nucleus transcriptomic landscape of primate hippocampal aging. In this study, the aged NHP hippocampus was found to demonstrate an array of aging-associated damages, including genomic and epigenomic instability, loss of proteostasis, as well as increased inflammation.

To explore unique cellular and molecular characteristics underlying these age-related phenotypes, scientists generated a high-resolution single-nucleus transcriptomic landscape of hippocampal aging in NHPs. It is composed of the gene expression profiles of 12 major hippocampal cell types, including neural stem cells, transient amplified progenitor cells (TAPC), immature neurons, excitatory/inhibitory neurons, oligodendrocytes, and microglia. Among them, TAPC and microglia were most affected by aging, as they manifested the most aging-related differentially expressed genes and those annotated as high-risk genes for neurodegenerative diseases.

In-depth analysis of the dynamic gene-expression signatures of the stepwise neurogenesis trajectory revealed the impaired TAPC division and compromised neuronal function, underlying the early onset and later stage of dysregulation in adult hippocampal neurogenesis, respectively. This landscape also helps to unveil contributing factors to a hostile microenvironment for neurogenesis in the aged hippocampus, namely the elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells. This may aggravate the loss of neurogenesis in the aged hippocampus, and may lead to the further decline of cognitive function and the occurrence of neurodegenerative diseases.

Link: https://www.eurekalert.org/news-releases/955145

The gut microbiome changes in detrimental ways with age. Beneficial populations decline in numbers while harmful populations gain ground at their expense. A large part of the harm done results from an increased burden of inflammatory microbes that aggravate the immune system, resulting in chronic inflammatory signaling that degrades tissue function throughout the body. But the loss of beneficial metabolites generated by microbial species is also increasingly well studied. Butyrate, for example, helps with cognitive function by upregulating BDNF expression, which in turn increases levels of neurogenesis.

In today's open access paper, researchers note an example of the opposite case, a harmful metabolite, isoamylamine, that produces cell death in microglia, a population of supporting immune cells in the brain. Production increases with age, and in aged mice at least, reducing levels of this one metabolite produces gains in cognitive function. We might take this as yet another piece of evidence supporting the value of rejuvenation of the gut microbiome, a goal that can be achieved all at once, rather than bit by bit, via strategies such as flagellin immunization or fecal microbiota transplantation. These approaches should receive more attention from the clinical community, as they can be carried out with little effort at the present time. Running small clinical trials to prove efficacy in human patients is a very feasible prospect, given funding for that project.

Gut bacterial metabolite promotes neural cell death leading to cognitive decline

Prior research has suggested a strong link between gut bacteria and brain health. In this new effort, the researchers looked into the possible impact on the brain of just one metabolite, isoamylamine (IAA), produced by one family of bacteria in the gut, Ruminococcaceae. They found first that IAA becomes more prevalent in the gut as people age due to the presence of more Ruminococcaceae. Their interest in IAA grew when they learned it could pass through the blood-brain barrier. They found the metabolite binds to a promoter region of the gene S100A8, which allowed for expression of the gene, resulting in production of apoptotic bodies, which lead to cell death. To learn more about what happens when such bindings occur, the researchers fed IAA to young healthy mice and determined that this resulted in a loss of cognitive function. They next blocked production of the metabolite in the guts of older mice and found that it led to improvements in cognitive performance.

Gut bacterial isoamylamine promotes age-related cognitive dysfunction by promoting microglial cell death

The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. Thus, our findings provide evidence that small molecules released from the gut microbiome can directly bind genomic DNA and act as transcriptional coregulators by recruiting transcription factors. These findings further unveil a molecular mechanism that connects gut metabolism to gene expression in the brain with implications for disease development.

Circadian mechanisms have been found to influence aging in short-lived species, though the degree to which this is relevant to treating aging in longer-lived species such as our own is up for debate. All too much of the metabolic response to stress, and items such as circadian rhythms that have an impact on that response, have far larger effects on the pace of aging in short-lived species than in long-lived ones. The work here, in which vision is found to alter circadian mechanisms and thus also the beneficial calorie restriction response, is interesting in the academic sense, in the same way that it is interesting that scent can disrupt the calorie restriction response, but most likely of little to no practical use.

Researchers conducted a broad survey to see what genes oscillate in a circadian fashion when flies on an unrestricted diet were compared with those fed just 10 percent of the protein of the unrestricted diet. Immediately, they noticed numerous genes that were both diet-responsive and also exhibiting ups and downs at different time points, or "rhythmic." They then discovered that the rhythmic genes that were activated the most with dietary restriction all seemed to be coming from the eye, specifically from photoreceptors, the specialized neurons in the retina of the eye that respond to light.

This finding led to a series of experiments designed to understand how eye function fit into the story of how dietary restriction can extend lifespan. For example, researchers set up experiments showing that keeping flies in constant darkness extended their lifespan. "That seemed very strange to us. We had thought flies needed the lighting cues to be rhythmic, or circadian." They then used bioinformatics to ask: Do the genes in the eye that are also rhythmic and responsive to dietary restriction influence lifespan? The answer was yes they do.

The biggest question raised by this work as it might apply to humans is, simply, do photoreceptors in mammals affect longevity? Probably not as much as in fruit flies, said Hodge, noting that the majority of energy in a fruit fly is devoted to the eye. But since photoreceptors are just specialized neurons, "the stronger link I would argue is the role that circadian function plays in neurons in general, especially with dietary restrictions, and how these can be harnessed to maintain neuronal function throughout aging."

Link: https://www.buckinstitute.org/news/buck-researchers-uncover-intriguing-connection-between-diet-eye-health-and-lifespan/

There have been signs that Saudi Arabian interests are considering putting significant amounts of funding into accelerating progress towards the treatment of aging, though it is entirely unclear as to whether any of that investment will be targeted towards the more useful areas of research and development, those focused on repair and reversal of age-related damage. This article is a decent high level summary of what may or may not come to pass via the Hevolution Foundation as a vehicle for the deployment of sovereign wealth into geroscience. The present accelerating trajectory for increased funding of translational aging research is clearly heading in this direction. Consider the few billion in funding devoted to reprogramming in just the last year or two. If not Saudi Arabia, then other countries will sooner or later devote large-scale funding towards the treatment of aging, in the hopes that it will prevent the collapse of entitlement systems due to the rising average age of the population.

Anyone who has more money than they know what to do with eventually tries to cure aging. Google founder Larry Page has tried it. Jeff Bezos has tried it. Tech billionaires Larry Ellison and Peter Thiel have tried it. Now the kingdom of Saudi Arabia, which has about as much money as all of them put together, is going to try it. The Saudi royal family has started a not-for-profit organization called the Hevolution Foundation that plans to spend up to $1 billion a year of its oil wealth supporting basic research on the biology of aging and finding ways to extend the number of years people live in good health, a concept known as "health span."

The foundation hasn't yet made a formal announcement, but the scope of its effort has been outlined at scientific meetings and is the subject of excited chatter among aging researchers, who hope it will underwrite large human studies of potential anti-aging drugs. The idea, popular among some longevity scientists, is that if you can slow the body's aging process, you can delay the onset of multiple diseases and extend the healthy years people are able to enjoy as they grow older. The fund is going to give grants for basic scientific research on what causes aging, just as others have done, but it also plans to go a step further by supporting drug studies, including trials of "treatments that are patent expired or never got commercialized."

The fund is authorized to spend up to $1 billion per year indefinitely, and will be able to take financial stakes in biotech companies. By comparison, the division of the US National Institute on Aging that supports basic research on the biology of aging spends about $325 million a year. Hevolution hasn't announced what projects it will back, but people familiar with the group say it looked at funding a $100 million X Prize for age reversal technology and has reached a preliminary agreement to fund the TAME trial, a test of the diabetes drug metformin in several thousand elderly people.

Link: https://www.technologyreview.com/2022/06/07/1053132/saudi-arabia-slow-aging-metformin/

Twenty years ago, there wasn't all that much of a difference between the public view of rejuvenation research and the cryonics field. Both were mocked by the mainstream media, marginal areas of human endeavor out on the fringes of society, supported by very little funding and a handful of dedicated supporters. Yet in both cases, compelling research existed to support the goals - of the treatment of aging, of reversible cryopreservation - and was largely ignored, or even actively derided by the academic mainstream, worried about appearances.

A great deal has changed since then for the field of rejuvenation research. In the early 2000s, patient advocates were delighted and surprised by the rare occasion on which a six or seven figure check arrived from a philanthropist. It didn't happen often! Twenty years down the line, however, and billions in funding from philanthropists, research institutions, and venture funds are now devoted to the development of in vivo epigenetic reprogramming as an approach to the treatment of aging. Similarly, hundreds of millions have been invested in the development of senolytic therapies to clear senescent cells. The treatment of aging as a medical condition and the goal of reversal of aging is no longer mocked, it is taken seriously, and both funding and the number of ventures are increasing at a rapid pace.

How did this change happen? It was a mix of networking, advocacy, philanthropy, and compelling advances in the science, such as the development of the first senolytics and many consequent studies showing rapid, profound rejuvenation in mice. A tipping point was reached after years of a long, slow grind of bootstrapping: a little more progress, a little more support, a little more progress. Once past that tipping point, matters moved much more rapidly year after year, and the acceleration continues today.

I recently attended the 50th anniversary conference for the Alcor Life Extension Foundation, celebrating the lengthy run of one of the oldest cryonics providers. A good deal of the discussion there orbited around the usual questions asked by a small and passionate community: how does the cryonics field become larger, more robust? How does it achieve greater funding and faster progress towards widespread use? Fifty years on from the very early days of improvised equipment, ad hoc science, and regulatory opposition, the field of cryonics now looks a lot like the field of rejuvenation biotechnology did fifteen or twenty years ago. Slow progress is underway, the organizations are far more professional, and a few visionary philanthropists are putting in six or seven figure checks occasionally. Compelling advances in research exist, and are not receiving the widespread attention that they deserve. New organizations for advocacy and research are being founded with small budgets and big visions. Some of the technology waiting in the wings, such as reversible vitrification of human organs, may help to reach the tipping point once they are fully realized and in widespread use.

Given this, I would not be surprised to see the cryonics field becoming much larger and more commercial, growing suddenly and rapidly, in the mid-to-late 2030s. By that time, I would expect that reversible vitrification of organs will be a going concern, radically changing the economics and viability of organ donation, and adopted as a core enabling technology by the new industry focused on manufacturing patient-matched organs to order. The widespread recognition of this technological capability will bring many more people to the realization that cryopreservation on clinical death is a viable approach to saving lives that would otherwise be lost, and matters will proceed ever more rapidly from there on.

Fecal microbiota transplantation from a young individual to an old individual has been shown in animal studies to reset the aging gut microbiome to a more youthful configuration for a lasting period of time. The gut microbiome changes in detrimental ways with age, harmful and inflammatory populations displacing beneficial populations that produce needed metabolites. A fecal microbiota transplant removes these changes, improving health, reducing inflammation, and extending life span in short-lived species. It is a procedure already used in humans, and which should be further developed as a means to improve the health of all older people.

Advanced maternal age is characterized by declines in the quantity and quality of oocytes in the ovaries, and the aging process is accompanied by changes in gut microbiota composition. However, little is known about the relationship between gut microbiota and ovarian aging. By using fecal microbiota transplantation (FMT) to transplant material from young (5-week-old) into aged (42-week-old) mice, we find that the composition of gut microbiota in FMT-treated mice presents a "younger-like phenotype" and an increase of commensal bacteria, such as Bifidobacterium and Ruminococcaceae. Moreover, the FMT-treated mice show increased anti-inflammatory cytokine IL-4 and decreased pro-inflammatory cytokine IFN-γ.

Fertility tests for assessing ovarian function reveal that the first litter size of female FMT-treated mice is significantly higher than that of the non-FMT group. Morphology analysis demonstrates a dramatic decrease in follicle atresia and apoptosis as well as an increase in cellular proliferation in the ovaries of the FMT-treated mice. Our results also show that FMT improves the immune microenvironment in aged ovaries, with decreased macrophages and macrophage-derived multinucleated giant cells (MNGCs). These results suggest that FMT from young donors could be a good choice for delaying ovarian aging.

Link: https://doi.org/10.1016/j.jgg.2022.05.006

Chronic inflammation disrupts tissue function throughout the body, contributing to the onset and progression of age-related conditions. One of the wide variety of ways in which this happens is via detrimental changes in stem cell populations and their activities. Researchers here focus down on mesenchymal stem cells in bone marrow as one example of many that might be considered. That senescent cells act to maintain an inflammatory environment is one of the reasons why removal of senescent cells produces profound and rapid rejuvenation in animal studies. More methods of cleanly reducing chronic inflammation with minimal side-effects are very much needed, a necessary part of the toolkit of rejuvenation therapies presently under development.

Mesenchymal stem cell (MSC) senescence is considered a contributing factor in aging-related diseases. We investigated the influence of the inflammatory microenvironment on bone marrow mesenchymal stem cells (BMSCs) under aging conditions and the underlying mechanism to provide new ideas for stem cell therapy for age-related osteoporosis. The BMSCs were cultured until passage 3 (P3) (young group) and passage 10 (P10) (aging group) in vitro. The supernatant was collected as the conditioned medium (CM). The young BMSCs were cultured in the CM of P3 or P10 cells. The effects of CM from different groups on the aging and stemness of the young BMSCs were examined. An inflammation assay was conducted on serum extracts from young (aged 8 weeks) and old (aged 78 weeks) mice, and differentially expressed factors were screened out.

We discovered that the CM from senescent MSCs changed the physiology of young BMSCs. Systemic inflammatory microenvironments changed with age in the mice. In particular, the pro-inflammatory cytokine IL-6 increased, and the anti-inflammatory cytokine IL-10 decreased. The underlying mechanism was investigated, and there was a change in the JAK-STAT signaling pathway, which is closely related to IL-6 and IL-10. Collectively, our results demonstrated that the age-related inflammatory microenvironment has a significant effect on the biological functions of BMSCs. Targeted reversal of this inflammatory environment may provide a new strategy for stem cell therapy to treat aging-related skeletal diseases.

Link: https://doi.org/10.3389/fbioe.2022.870324

Atherosclerosis is a condition of dysfunctional macrophages. The innate immune cells called macrophages are responsible for removing cholesterol from blood vessel walls, where it lodges, carried by LDL particles. The macrophages ingest cholesterol and hand it off to HDL particles that carry it back to the liver for excretion. Macrophages exhibit packages of behaviors called polarizations, and this cleaning up of cholesterol is associated with the pro-regenerative, anti-inflammatory M2 polarization. Atherosclerosis is an inflammatory condition in the sense that chronic inflammation biases macrophages into the pro-inflammatory M1 polarization, in which they no longer attempt to clear cholesterol.

The formation of atherosclerotic lesions, fatty deposits that narrow and weaken blood vessels, occurs when macrophages are hampered enough to cross the tipping point of clearing cholesterol more slowly than it accumulates. Once a lesion forms in earnest, it becomes a toxic, inflammatory microenvironment itself, capable of overwhelming the macrophages sent to clean it up. Systemic inflammation, oxidative stress, and related body-wide issues associated with aging, obesity, and diabetes make that tipping point more easily reached.

Senescent cells contribute to chronic inflammation via the senescence-associated secretory phenotype (SASP), a mix of pro-growth, pro-inflammatory signal molecules that are harmful to tissue function when sustained over the long term. At least some of the dysfunctional macrophages present in atherosclerotic lesions are senescent, and hamper the efforts of other nearby macrophages, but the burden of senescent cells throughout the body is also a problem, given that it contributes to an environment that biases macrophages away from attempting to clear cholesterol from blood vessel walls.

The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities

The SASP contributes to the secretion of inflammatory cell cytokines and chemokines that induce local and systemic inflammatory responses, immune system activation, tissue damage and fibrosis, and cell apoptosis and dysfunction. Moreover, the SASP can also induce the enlargement of local and systemic senescence to neighbouring cells via paracrine or endocrine mechanisms. Furthermore, a variety of molecules involved in the SASP can serve as promoters and biomarkers of cardiovascular diseases including atherosclerosis.

Recent clinical trials have clearly demonstrated a causal relationship between inflammation and human atherosclerosis. Atherosclerosis is considered a chronic inflammatory disease, and atherosclerotic plaques present with cell senescence. Cell senescence and atherosclerosis have multiple common aetiological stimuli, but senescent cells are not just simple bystanders. Senescent cells from atherosclerotic plaques lack proliferation, overexpress P16INK4A, P53, P21, and increase the activity of senescence-associated beta-galactosidase (SAβG). They can also establish the SASP, which can cause increased secretion of various inflammatory cell cytokines, chemokines and matrix-degrading proteases. Notably, there is evidence that the SASP, as a source of chronic inflammation and some plaque instability factors, is involved in the pathogenesis and development of atherosclerosis.

The SASP from senescent cells exerts many pro-atherogenic effects, which may involve vascular remodelling, plaque formation and rupture. There is evidence that plaque-rich arteries contain various typical SASP components, including matrix metalloproteinases and multiple inflammatory factors. However, these phenomena are not present in normal adjacent blood vessels. Senescent cells in blood vessels with the SASP release various inflammatory cytokines (interleukin-6 and interleukin-8) and growth factors (such as VEGF, PDGF, chemokines and matrix metalloproteinases). Studies have shown that some of these are known cardiovascular risk factors. Additionally, a study reported that p16 positive cells are the main driver of the aged heart phenotype that causes a reduced lifespan in mice, so removing senescent cells with p16 promoter activity can inhibit the occurrence and development of atherosclerotic plaques and improve the stability of plaques

Therefore, the prevention of accelerated cellular senescence and the SASP represents an important therapeutic opportunity, and understanding the mechanisms responsible for this change is essential for the promotion of prevention and therapy of atherosclerosis and other age-associated diseases.

A number of approaches that improve mitochondrial function to produce benefits in aging mice, while comparing poorly with exercise as an intervention in humans, appear to work by improving mitophagy. That includes mitochondrially targeted antioxidants such as mitoQ, approaches to NAD+ upregulation such as nicotinamide riboside, and so forth. Mitophagy is the quality control process that identifies worn and damaged mitochondria, and moves them to a lysosome for recycling. Every cell contains hundreds of mitochondria, responsible for generating chemical energy store molecules to power cellular operations. Dysfunctional mitophagy leads to an accumulation of dysfunctional mitochondria. A loss of efficiency in mitophagy occurs with age, and thus there is interest in the scientific community in producing ways to improve this situation. So far, however, the practical outcome of such research has been underwhelming, sirtuins included.

Since sirtuins were found to extend the lifespan of Saccharomyces cerevisiae and Caenorhabditis elegans, the mechanism of sirtuin lifespan extension and whether it can extend the lifespan of other species has been actively studied. With increasing research in the last 5 years, sirtuins are increasingly recognized as being critical for regulating mitophagy and maintaining mitochondrial homeostasis. Taken together, the sirtuin family can activate or inhibit mitophagy through multiple pathways, for instance deacetylation of PGC-1α and FOXO1/FOXO3 and reduction of reactive oxygen species, thereby affecting aging and age-related diseases. By targeting these pathways, it may be possible to delay aging.

A consensus has now emerged from many studies of sirtuin activators that sirtuins mediated aspects of caloric restriction. Sirtuin activators can modulate aging and age-related diseases by activating a variety of sirtuin-induced biological functions, and have demonstrated significant aging delay and disease mitigation in experimental models. Excitingly, some sirtuin activators are already in clinical trials. For example, resveratrol acts in neurological diseases, SRT2104 in inflammation, and nicotinamide riboside in the cardiovascular system. Furthermore, decreased NAD+ levels during aging reduce sirtuin activity, which may contribute to the aging process.

However, there are still many unresolved issues. First, while there is substantial evidence implicating sirtuins in delayed aging and suppression of the aging phenotype through activation of mitophagy, there are few experiments directly demonstrating this pathway. Secondly, the effects of different sirtuin family members on mitophagy and the mechanisms of sirtuin-induced mitophagy in aging remain poorly understood. Sirtuin family members are redundant in regulating lifespan and whether other enzyme activities (excluding acetylation activity) are involved in the aging process. Thirdly, sirtuin in different tissues seems to have different effects. The specificity of sirtuin-induced mitophagy for different aging tissues and age-related diseases also merits further investigation. Fourthly, cancer cells often use mitophagy to maintain their metabolic reprogramming and growth. This is a negative effect of sirtuin-mediated mitophagy. This raises the question that whether activation of mitophagy promotes the growth of cancer cells. Fifthly, it is still unclear about the pharmacokinetics and pharmacodynamics of sirtuin activator NAD+ precursors and the mechanism of their transport through cell membranes into the blood and cells. Hopefully, these questions will be addressed in the future and provide a clearer direction for delaying human aging.

Link: https://doi.org/10.3389/fnagi.2022.845330

A range of processes are involved in age-related stiffening of blood vessel walls. Cross-linking in the extracellular matrix leads to a loss of elasticity, as does disruption of elastin structures. In addition, inflammation and other issues cause dysfunction in the vascular smooth muscle cells responsible for contraction and dilation. Stiffness leads to hypertension, which in turn causes structural damage to delicate tissues throughout the body. Thus there is a strong incentive to better understand why stiffening occurs, and identify which of the various processes are most important and most amenable to interventions that might reverse this aspect of aging.

Arterial stiffness (AS) is one of the earliest detectable signs of structural and functional alterations of the vessel wall and an independent predictor of cardiovascular events and death. The emerging field of metabolomics can be utilized to detect a wide spectrum of intermediates and products of metabolism in body fluids that can be involved in the pathogenesis of AS. Research over the past decade has reinforced this idea by linking AS to circulating acylcarnitines, glycerophospholipids, sphingolipids, and amino acids, among other metabolite species.

Some of these metabolites influence AS through traditional cardiovascular risk factors (e.g., high blood pressure, high blood cholesterol, diabetes, smoking), while others seem to act independently through both known and unknown pathophysiological mechanisms. We propose the term 'arteriometabolomics' to indicate the research that applies metabolomics methods to study AS. The 'arteriometabolomics' approach has the potential to allow more personalized cardiovascular risk stratification, disease monitoring, and treatment selection. One of its major goals is to uncover the causal metabolic pathways of AS. Such pathways could represent valuable treatment targets in vascular ageing.

Link: https://doi.org/10.3390/metabo12050370

The brain is a very complex organ, and thus the age-related failures of brain function also tend to be very complex. Alzheimer's disease receives the greatest attention from the research community, but is still only partially understood. The major focus of efforts over the past two decades has been on the clearance of amyloid-β aggregates from the brain, largely via immunotherapies, but a few other approaches have surfaced as well. Only in the past few years has this effort achieved success and resulted in large reductions in amyloid-β in patient brains, but unfortunately this did not result in a reversal of symptoms.

The amyloid cascade hypothesis is the central dogma for the study of Alzheimer's disease: amyloid-β aggregation occurs slowly over time, setting up the conditions for the later, more harmful stage of neuroinflammation and tau aggregation. That amyloid-β clearance fails to help patients may indicate that amyloid-β becomes irrelevant in the later stages of Alzheimer's disease, or it may indicate that it is not actually central to the progression of Alzheimer's disease. Over the years of failure to make meaningful progress with clearance of amyloid-β, and especially now that clearance has failed to help patients, researchers have increasingly turned to other approaches. This is a field in the midst of profound change and loud debate.

Given what has been discovered about the role of senescent cells in the aging brain in recent years, and the growing evidence for chronic inflammation to occupy a central position in the progression of neurodegenerative conditions, it seems likely that clearance of senescent cells is one of the most promising new approaches to Alzheimer's disease currently in the works. Time will tell; the first trial using the senolytic dasatinib and quercetin combination is underway.

Impact of New Drugs for Therapeutic Intervention in Alzheimer's Disease

The treatments of Alzheimer's disease (AD) fall into two main categories: symptomatic and disease-modifying. The purpose of symptomatic treatments is cognitive improvement or control of neuropsychiatric symptoms, without having an impact on the biological causes leading to neuronal death. By contrast, disease-modifying treatments are designed to induce neuroprotection through changing the neuropathology of AD, often acting on a variety of intermediate mechanisms. Unfortunately, most therapeutic agents developed in the last 15 years have failed.

Despite being such an important disease, the number of drugs in development for AD is much lower than in other diseases with a higher therapeutic arsenal. This reflects the fact that AD's biology is poorly understood, and the availability of biomarkers is a very limited. Moreover, the duration of clinical trials for assessing AD treatments is very long, which increases the risk of failure.

In any case, we may wonder why the treatments in development are failing or are not effective. Based on numerous trials of failed drugs in patients with AD, a plausible explanation could be that amyloid-β (Aβ) therapies are being administered too late, when the disease is completely developed and the effectiveness of the treatments is dramatically reduced. Therefore, an earlier (pre-symptomatic) diagnosis should be made, including a rethinking of the AD diagnostic criteria, which should be based primarily on biomarkers. Following this line of thought, drugs in phase III clinical development are being tested primarily in subjects during the early stages of the disease (mild cognitive impairment), in the preclinical phase of AD or even in asymptomatic subjects at high risk of developing AD.

An additional explanation could be that the initial hypotheses proposed for β-amyloid and tau as the main responsible neurotoxins for AD, are not able to entirely explain the pathophysiology of the disease. Hence, β-amyloid plaques and neurofibrillary tangles would have a secondary role in AD's origin. Indeed, if we review the clinical trials developed during the last 5 years, we find a progressive emphasis on non-amyloid targets, including candidate treatments for inflammation, synapse and neuronal protection, vascular factors, neurogenesis, and epigenetic interventions. There has also been an increase in the study of "reused drugs", that is to say, drugs that are used to treat other pathologies but are also thought to be useful for AD treatment. Two clear examples of these are escitalopram and metformin. In any case, the complexity of AD's etiopathogenesis demands multiple therapeutic strategies that can be proposed according to the molecular and physiological processes involved.

Undoubtedly, the trends in therapeutic strategies for AD will involve an increase in the diversity of non-amyloid or tau targets, including inflammation, insulin resistance, synapse and neuronal protection, cardiovascular factors, neurogenesis and epigenetic interventions. Indeed, some authors consider that AD should no longer be considered a brain disease, since its development is also attributed to peripheral factors as, for instance, intestinal dysbiosis.

Researchers here note a correlation between cancer diagnosis and greater risk of later onset of type 2 diabetes. A reasonable guess is that this is mediated by the increased burden of cellular senescence produced by chemotherapy and radiotherapy, though, as the researchers point out, the widely different risks by cancer type may indicate that tumors are metabolically active in ways that specifically promote the metabolic dysfunction that leads to type 2 diabetes.

For patients with cancer, prevalent type 2 diabetes at the date of cancer diagnosis is associated with increased cancer-specific and all-cause mortality. Yet, despite potential health implications, there is limited knowledge on whether cancer is also a risk factor for type 2 diabetes. We investigated the incidence of type 2 diabetes following a cancer diagnosis and evaluated the influence of new-onset type 2 diabetes in patients with cancer on overall survival.

We included 51,353 incident cancer case subjects diagnosed from 2004 to 2015 living in the Greater Copenhagen area without type 2 diabetes. We sampled all 112 million tests from 1.3 million individuals, performed by the Copenhagen General Practitioners' Laboratory, contained in the Copenhagen Primary Care Laboratory Database (CopLab) (2015-57-0121) from 2000 to 2015, data for which were merged with data on incident cancer from the Danish Cancer Registry. The median follow-up time was 2.34 years for all case subjects and 4.41 years for cancer-free control subjects.

We found an increased hazard of new-onset type 2 diabetes for all cancers (hazard ratio [HR] 1.09). The hazard of new-onset type 2 diabetes for different cancer types in comparisons with control subjects was particularly strong for pancreatic cancer (HR 5.00), cancer of the brain and other parts of the nervous system (HR 1.54), and cancer of the corpus uteri (HR 1.41). Patients diagnosed with lung (HR 1.38), urinary tract (HR 1.32), and breast (HR 1.20) cancers also had a significantly increased hazard of type 2 diabetes.

Our results align with a smaller study of 15,130 incident cancer survivors where investigators observed an overall 35% increase in the hazard of diabetes following a cancer diagnosis. We included more than three times the number of incident cancer cases and observed similar effects; thus, our findings bolster the evidence for associations that was previously less strongly supported. The underlying mechanisms still remain to be defined but could include common risk factors, tumor-secreted factors, or effects of treatment.

Link: https://doi.org/10.2337/dc22-0232

Researchers here suggest that the amyloid-β aggregates characteristic of Alzheimer's disease first originate inside cells, and are connected with lysosomal dysfunction. Only later do the better studied toxic extracellular aggregates form. This is not the first group to point out that intracellular amyloid-β may be important. It is early days for this line of research, and quite unclear as to how this might change strategies aimed at disrupting the early stages of the condition, prior to symptoms, a period of years in which amyloid-β aggregates are accumulating slowly over time.

Study findings argue that neuronal damage characteristic of Alzheimer's disease takes root inside cells and well before these thread-like amyloid plaques fully form and clump together in the brain. The study traced the root dysfunction observed in mice bred to develop Alzheimer's disease to the brain cells' lysosomes. These are small sacs inside every cell, filled with acidic enzymes involved in the routine breakdown, removal, and recycling of metabolic waste from everyday cell reactions, as well as from disease. Lysosomes are also key, researchers note, to breaking down and disposing of a cell's own parts when the cell naturally dies.

As part of the study, researchers tracked decreasing acid activity inside intact mouse cell lysosomes as the cells became injured in the disease. Imaging tests developed to track cellular waste removal showed that certain brain cell lysosomes became enlarged as they fused with so-called autophagic vacuoles filled with waste that had failed to be broken down. These autophagic vacuoles also contained earlier forms of amyloid beta. In neurons most heavily damaged and destined for early death as a result, the vacuoles pooled together in "flower-like" patterns, bulging out from the cells' outer membranes and massing around each cell's center, or nucleus. Accumulations of amyloid beta formed filaments inside the cell, another hallmark of Alzheimer's disease. Indeed, researchers observed almost-fully formed plaques inside some damaged neurons.

"Previously, the working hypothesis mostly attributed the damage observed in Alzheimer's disease to what came after amyloid buildup outside of brain cells, not before and from within neurons. This new evidence changes our fundamental understanding of how Alzheimer's disease progresses; it also explains why so many experimental therapies designed to remove amyloid plaques have failed to stop disease progression, because the brain cells are already crippled before the plaques fully form outside the cell."

Link: https://www.eurekalert.org/news-releases/954383

In today's research materials, scientists present data on clonal hematopoiesis with age in humans. Hematopoiesis is the creation of blood and immune cells, taking place in the bone marrow. Clonal hematopoiesis of indeterminate potential (CHIP) is the name given to one of the age-related changes taking place in the populations of stem cells and progenitor cells that carry out hematopoiesis. Stochastic mutations occur constantly in the body. In the dynamic hematopoietic cell populations of the bone marrow, some of these mutations allow the mutated cells to outcompete their undamaged peers to make up a much larger fraction of the population than would otherwise be the case. Thus, with advancing age, an increasing proportion of the immune cells in the body originate from just a few clonally expanded, mutated hematopoietic populations.

Where these mutations predispose cells to cancerous behavior, then this is clearly an issue. CHIP is a known precursor to leukemia and similar conditions. It is less clear as to why CHIP is associated with other aspects of aging, such as atherosclerosis and consequent cardiovascular disease. Arguments based on mutations increasing predisposition to inflammatory behavior in immune cells seem reasonable, but, as ever, more data is needed.

What to do about all of this? The research community is heading in the direction of restoring disrupted hematopoiesis in older people as a part of improving immune function in the elderly. Some approaches, such as transplantation of new hematopoietic cells, may effectively address CHIP if carried out in the right way. Approaches that involve restoration of function in the existing population by adjusting cell behavior, such as CD42 inhibition, have been shown to produce benefits in animal models, but they could also make CHIP worse if they give further advantage to a mutated hematopoietic population. With that in mind, it would be advantageous to be able to avoid the need to outright replace stem cell populations, given the challenges involved, and focus on small molecule and similar, easier modes of treatment. Unfortunately, cell replacement may turn out to be necessary in this context.

Cellular secrets of ageing unlocked by researchers

Researchers studied the production of blood cells from the bone marrow, analysing 10 individuals ranging in age from new-borns to the elderly. They sequenced the whole genomes of 3,579 blood stem cells, identifying all the somatic mutations contained in each cell. The team used this to reconstruct 'family trees' of each person's blood stem cells, showing, for the first time, an unbiased view of the relationships among blood cells and how these relationships change across the human lifespan.

The researchers found that these 'family trees' changed dramatically after the age of 70 years. The production of blood cells in adults aged under 65 came from 20,000 to 200,000 stem cells, each of which contributed in roughly equal amounts. In contrast, blood production in individuals aged over 70 was very unequal. A reduced set of expanded stem cell clones - as few as 10 to 20 - contributed as much as half of all blood production in every elderly individual studied. These highly active stem cells had progressively expanded in numbers across that person's life, caused by a rare subset of somatic mutations known as 'driver mutations'.

These findings led the team to propose a model in which age-associated changes in blood production come from somatic mutations causing 'selfish' stem cells to dominate the bone marrow in the elderly. This model, with the steady introduction of driver mutations that cause the growth of functionally altered clones over decades, explains the dramatic and inevitable shift to reduced diversity of blood cell populations after the age of 70. Which clones become dominant varies from person to person, and so the model also explains the variation seen in disease risk and other characteristics in older adults.

Clonal dynamics of haematopoiesis across the human lifespan

Age-related change in human haematopoiesis causes reduced regenerative capacity, cytopenias, immune dysfunction, and increased risk of blood cancer, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production.

Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

It is by now well-recognized that chronic inflammation is an important contributing cause of many common age-related diseases. Osteoarthritis is one of these, in which the maintenance of joint tissue is disrupted by unresolved inflammatory signaling. Reduction of inflammation is an important goal, but to date the interventions that can achieve this outcome are comparatively crude, a blockade of specific signal molecules that suppresses some degree of both excessive and necessary inflammatory responses. The long term side-effects of an immune system suppressed in this way are undesirable and include an increased vulnerability to pathogens. Clearance of senescent cells with senolytic therapies, removing their always-on pro-inflammatory signaling, represents the first approach to the suppression of inflammation that dampens only excess inflammation. We can hope that the future brings more such technologies.

Osteoarthritis (OA) is a musculoskeletal disease characterized by cartilage degeneration and stiffness, with chronic pain in the affected joint. It has been proposed that OA progression is associated with the development of low-grade inflammation (LGI) in the joint. In support of this principle, LGI is now recognized as the major contributor to the pathogenesis of obesity, aging, and metabolic syndromes, which have been documented as among the most significant risk factors for developing OA. These discoveries have led to a new definition of the disease, and OA has recently been recognized as a low-grade inflammatory disease of the joint.

Damage-associated molecular patterns (DAMPs), or alarmin molecules, the major cellular components that facilitate the interplay between cells in the cartilage and synovium, activate various molecular pathways involved in the initiation and maintenance of LGI in the joint, which, in turn, drives OA progression. A better understanding of the pathological mechanisms initiated by LGI in the joint represents a decisive step toward discovering therapeutic strategies for the treatment of OA. Recent findings and discoveries regarding the involvement of LGI mediated by DAMPs in OA pathogenesis are discussed. Modulating communication between cells in the joint to decrease inflammation represents an attractive approach for the treatment of OA.

Link: https://doi.org/10.3390/biomedicines10051109

The innate immune cells known as macrophages are critical to the progression of atherosclerosis. These cells are responsible for ingesting the excess cholesterol in blood vessel walls and returning it to the bloodstream for passage to the liver and excretion. When they falter in this task, atherosclerotic lesions develop, leading to narrowed blood vessels and ultimately a stroke or heart attack. Once a significant lesion is in place, it becomes a source of inflammation, attracting ever more macrophages to arrive, be overwhelmed by excessive cholesterol, and die, adding their mass to the growing lesion.

Macrophages can adopt different packages of behaviors, or polarizations, in response to circumstances. M1 is an inflammatory, aggressive state, focused on hunting down pathogens, while M2 is anti-inflammatory and regenerative, focused on tissue maintenance. A part of the problem in atherosclerosis, and why atherosclerosis an age-related condition, is that macrophages are biased to the M1 polarization by the aged, inflammatory environment, rather than to the useful M2 behaviors needed to clear up blood vessel walls. This is only part of the problem, however.

The implication of the heterogeneous spectrum of pro- and anti-inflammatory macrophages (Macs) has been an important area of investigation over the last decade. The polarization of Macs alters their functional phenotype in response to their surrounding microenvironment. Macs are the major immune cells implicated in the pathogenesis of atherosclerosis. A hallmark pathology of atherosclerosis is the accumulation of pro-inflammatory M1-like macrophages in coronary arteries induced by pro-atherogenic stimuli; these M1-like pro-inflammatory macrophages are incapable of digesting lipids, thus resulting in foam cell formation in the atherosclerotic plaques.

Recent findings suggest that the progression and stability of atherosclerotic plaques are dependent on the quantity of infiltrated Macs, the polarization state of the Macs, and the ratios of different types of Mac populations. The polarization of Macs is defined by signature markers on the cell surface, as well as by factors in intracellular and intranuclear compartments. At the same time, pro- and anti-inflammatory polarized Macs also exhibit different gene expression patterns, with differential cellular characteristics in oxidative phosphorylation and glycolysis. Macs are reflective of different metabolic states and various types of diseases.

In this review, we discuss the major differences between M1-like Macs and M2-like Macs, their associated metabolic pathways, and their roles in atherosclerosis. Mechanisms that minimize Mac inflammation, increase lipid degradation, and prevent foam cell formation, are likely to decrease atherosclerosis progression. Future works are needed to further elucidate the mechanisms of actions by which different factors induce inflammatory or anti-inflammatory Macs in the context of foam cell formation. A better understanding of Mac infiltration, differentiation, polarization, and phagocytosis would be extremely beneficial for the prevention and treatment of atherosclerosis.

Link: https://doi.org/10.3390/genes13050756

Genetic differences are definitively the cause of differences in life span between species, self-evidently so. But within our own species, a few decades of earnest investigation has failed to turn up much evidence for genetic variants to be all that important in determining natural variation in human life span. If anything, the development of large genetic databases, such as the UK Biobank, has led to a reduction in the estimated contribution of genetic variation to life span variation. Near all associations between gene variants and longevity have tiny effect sizes, and also fail to replicate in other study populations, suggesting that there is little here to find, or at best a landscape of thousands of variants with small, interacting effects.

Thus for the vast majority of people, life span appears to be near entirely the result of lifestyle choices, such as weight and fitness, and environmental factors, such as exposure to persistent pathogens. Even the few known longevity-associated genes have very small effects on survival to late life. This means that even were everyone equipped with such variants, or drugs that mimicked the effects of these variants, then survival odds would still be very low. If we want more than this when it comes to ways to extend healthy life span, then it must come from medical technologies that repair the damage of aging, not ways to emulate specific genetic variants.

How Important Are Genes to Achieve Longevity?

Several studies on the genetics of longevity have been reviewed in this paper. The results show that, despite the efforts made by the international scientific community and the use of high-throughput genotyping methodologies, satisfactory results have not been obtained. The most significant associations have been obtained with the two genes, APOE and FOXO3A, which had already been identified for some time with simple case-control studies. From the evolutionary point of view, longevity depends on the residual maintenance functions after the end of the reproduction period. Aging depends on stochastic events and the aging phenotype is the result of the accumulation of cellular damage that cannot be repaired by the cellular maintenance systems that are running out. Therefore, longevity depends on the possibility of survival after the end of the reproductive period and the genes that lead to longevity are "survival genes" rather than "longevity genes".

Several studies of formal genetics strongly suggest the role of genes in achieving longevity. The comparison between the survival of the siblings of centenarians and that of their brothers-in-law, who likely shared the same lifestyle for most of their lives, showed that "the survival advantage" of siblings of long-lived subjects was not fully shared from their brothers-in-law. This suggested that beyond the family environment, there are genetic factors that influence survival and, consequently, longevity. This was not true comparing the survival of sisters with that of sisters-in-law. Interestingly, in this study, the survival curve of the sisters of long-lived subjects did not differ from the one of sisters-in-law, suggesting that the genetic component explains longevity in men more than in women. The genetic component of lifespan in humans has also been analyzed by comparing the age of death of monozygotic and dizygotic twins. This has allowed to estimate that about 25% of the variation in human longevity can be due to genetic factors and indicated that this component is higher at older ages and is more important in males than in females.

It is thought that for the first eight decades of life, a correct lifestyle is a stronger determinant of health and life span than genetics. Genetics then appears to play a progressively important role in keeping individuals healthy and live as they age into their eighties and beyond. For centenarians, it reaches up to 33% for women and 48% for men. However, in general, the effect sizes were not large, suggesting that many genes of small effect play a role, as indeed in all multifactorial traits; however, it needs to be considered that there is a dynamic interplay between genetic and environmental variations in the development of individual differences in health, and hence, longevity. Therefore, it is not surprising that GWAS-replicated associations of common variants with longevity have been few since they pool different populations losing the "ecological" dimension of longevity.

Overall, the findings discussed in this paper strongly suggest that longevity genetics are closely associated with protection against age-related diseases, particularly cardiovascular diseases (CVDs). The association with longevity is not surprising because CVDs are the leading cause of death globally, with an estimated 17.9 million deaths annually.

You may recall a recent study in which researchers showed that low dose chloroquine modestly slows aging in rats. Here, an analogous study in mice produces a similar result. This outcome is interesting given that chloroquine inhibits cellular maintenance processes, such as autophagy, that are required for many of the interventions shown to slow aging, such as the practice of calorie restriction. The authors present a range of data on various aspects of mouse biochemistry relevant to aging, but how exactly chloroquine is acting to slow aging, and in ways that outweigh a reduction in normal cellular maintenance, remains up for debate. The prior study pointed to a reduction in cellular senescence and inflammation, but that analysis was not carried out here.

Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. Since spermidine increases autophagy, we asked if treatment with chloroquine, an inhibitor of autophagy, would shorten the lifespan of mice. Recently, chloroquine has intensively been discussed as a treatment option for COVID-19 patients. To rule out unfavorable long-term effects on longevity, we examined the effect of chronic treatment with chloroquine given in the drinking water on the lifespan and organ pathology of male middle-aged NMRI mice. We report that, surprisingly, daily treatment with chloroquine extended the median life span by 11.4% and the maximum life span of the middle-aged male NMRI mice by 11.8%.

Subsequent experiments show that the chloroquine-induced lifespan elevation is associated with dose-dependent increase in LC3B-II, a marker of autophagosomes, in the liver and heart that was confirmed by transmission electron microscopy. This supports the hypothesis that long-term treatment led to an accumulation of autophagosomes due to impaired autophagosome fusion with lysosomes. Quite intriguingly, chloroquine treatment was also associated with a decrease in glycogenolysis in the liver suggesting a compensatory mechanism to provide energy to the cell. Accumulation of autophagosomes was paralleled by an inhibition of proteasome-dependent proteolysis in the liver and the heart as well as with decreased serum levels of insulin growth factor binding protein-3 (IGFBP3), a protein associated with longevity. We propose that inhibition of proteasome activity in conjunction with an increased number of autophagosomes and decreased levels of IGFBP3 might play a central role in lifespan extension by chloroquine in male NMRI mice.

Link: https://doi.org/10.18632/aging.204069

Researchers here make a few interesting observations on gene expression data from a range of mammalian species with very different life spans. Longer-lived species exhibit weaker inflammatory responses and more effective DNA repair, for example. Chronic inflammation is a feature of aging, as the immune system reacts to molecular damage and the presence of increasing numbers of senescent cells. Unresolved inflammatory signaling is disruptive to cell behavior and tissue function throughout the body, and is implicated in the onset and progression of all of the common age-related conditions.

Researchers compared the gene expression patterns of 26 mammalian species with diverse maximum lifespans, from two years (shrews) to 41 years (naked mole rats). They identified thousands of genes related to a species' maximum lifespan that were either positively or negatively correlated with longevity. They found that long-lived species tend to have low expression of genes involved in energy metabolism and inflammation; and high expression of genes involved in DNA repair, RNA transport, and organization of cellular skeleton (or microtubules).

Previous researchhas shown that features such as more efficient DNA repair and a weaker inflammatory response are characteristic of mammals with long lifespans. The opposite was true for short-lived species, which tended to have high expression of genes involved in energy metabolism and inflammation and low expression of genes involved in DNA repair, RNA transport, and microtubule organization.

When the researchers analyzed the mechanisms that regulate expression of these genes, they found two major systems at play. The negative lifespan genes - those involved in energy metabolism and inflammation - are controlled by circadian networks. That is, their expression is limited to a particular time of day, which may help limit the overall expression of the genes in long-lived species. On the other hand, positive lifespan genes - those involved in DNA repair, RNA transport, and microtubules - are controlled by what is called the pluripotency network. The pluripotency network is involved in reprogramming somatic cells into embryonic cells, which can more readily rejuvenate and regenerate, by repackaging DNA that becomes disorganized as we age.

Link: https://www.rochester.edu/newscenter/the-secret-to-a-longer-lifespan-gene-regulation-holds-a-clue-523672/

In today's open access paper, researchers map out the various epithelial progenitor cell populations responsible for producing and then maintaining the thymus, finding that these cells are quite diverse, with several types participating at different times during development and adult life. The thymus is of great interest in the context of aging because (a) it is where thymocytes mature into T cells of the adaptive immune system, and (b) it atrophies with age, active tissue replaced by fat, and the supply of new T cells greatly diminished. This is one of the major contributions to the age-related decline of the immune system. A better understanding of how the thymus is maintained could lead to novel approaches to regeneration, and maintenance of immune competence into later life.

Numerous efforts have been made to identify a viable approach to regrow the thymus in adult humans. One of these is delivery of fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF). A good number of studies demonstrate that this approach can provoke regrowth of the adult thymus in animals. Today's paper adds to this body of knowledge by showing that life-long overexpression of KGF in genetically engineered mice produces a thymus that remains large into later life, and does so without exhausting the progenitor cell populations responsible for maintaining this tissue. Unfortunately the side-effects of KGF make it impossible to deliver large enough doses systemically in humans to produce the same outcome. A clinical trial in HIV patients failed for this reason. Direct injection of the thymus would work to put enough KGF in the right place, but it is likely only palatable to regulators in cases of severe illness, given the small risk of serious harm that accompanies deep organ injection, particularly in older people.

Secrets of thymus formation revealed

Rsearchers have now succeeded in describing the unexpected diversity of thymic epithelial cells at the transcriptional level. Algorithms developed for the precise description of differences in the gene activity of individual cells made it possible to identify potential precursor cells. As a result, for the first time it became possible to study the development of thymic epithelium at different ages in equisite molecular detail. This kind of analysis is of particular interest to immunologists because the thymus is subject to significant changes during life. Rapid organ growth and massive T-cell production are characteristic of the early developmental stages. In contrast, there is a gradual loss of functional thymic epithelial cells in old age and, therefore, decreased T-cell production. These age-related changes are associated with a reduced immune function.

The researchers identified two bipotent progenitor populations of the thymic epithelium in their analysis. An "early" progenitor population takes over the primary role in the thymus formation during embryonic development. While in the juvenile organism, a subsequent "postnatal" progenitor population significantly determines the continued thymus formation in adulthood.

Developmental dynamics of two bipotent thymic epithelial progenitor types

T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells (TECs) and diminished naive T cell production with age. Here we combine scRNA-seq and a new CRISPR-Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium.

We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without transgenicexhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity. Mice treated with pharmacological doses of the Fgfr2b ligand KGF, the human homologue of Fgf7, exhibit an increase in the number of TECs. However, it is not known whether Fgf stimulation targets progenitors, mature TECs, or both. To examine this question, we generated several mouse models for continuous autocrine provision of an Fgfr2b ligand in the thymus. We established that, under physiological conditions, the extent of Fgf signalling in TECs is determined by limiting levels of ligands, rather than the receptor; notably, we found that pharmacological supplementation of the Fgfr2b ligand Fgf7 could be mimicked in vivo by ectopic expression of Fgf7 in the TECs of transgenic mice. Continuous autocrine provision of Fgf7 within the epithelial compartment in this transgenic model increased the number of TECs and thymocytes and resulted in a massive and sustained increase in thymus size.

The raised blood pressure of hypertension causes structural damage to tissues throughout the body. In the brain it leads to disruption of the blood-brain barrier, and consequent passage of inflammatory molecules into the brain, as well as an increased pace of rupture of small blood vessels, creating tiny areas of permanent damage. This is a matter of damage accumulating over time. Higher blood pressure implies a faster pace of damage accumulation, while a longer period of raised blood pressure implies a larger amount of damage overall. Thus, as noted here, the duration of hypertension correlates with dementia risk and mortality, a result of the damage done by raised blood pressure.

Elevated blood pressure (BP) has been linked to impaired cognition and dementia in older adults. However, few studies have accounted for long-term cumulative BP exposure. The aim of this study was to test whether long-term cumulative BP was independently associated with subsequent cognitive decline, incident dementia, and all-cause mortality among cognitively healthy adults. This study used data from the HRS (Health and Retirement Study) and ELSA (English Longitudinal Study of Ageing). A total of 7,566 and 9,294 participants from ELSA and the HRS were included, with a median age of 62.0 years.

The median follow-up duration was 8.0 years. Elevated cumulative systolic BP and pulse pressure were independently associated with accelerated cognitive decline, elevated dementia risk, and all-cause mortality. In conclusion, long-term cumulative BP was associated with subsequent cognitive decline, dementia risk, and all-cause mortality in cognitively healthy adults aged ≥50 years. Efforts are required to control long-term systolic BP and pulse pressure and to maintain adequate diastolic BP.

Link: https://doi.org/10.1016/j.jacc.2022.01.045

Researchers here note that circular RNAs are differentially expressed in long-lived individuals. This assessment is very much a first step on the lengthy road of determining whether or not circular RNAs are interesting in the context of aging and longevity. Since everything is connected to everything else in cellular biochemistry, an exceedingly complex web of interactions, most of the observed differences between long-lived people and others will be unimportant downstream effects, not directly connected to aging and longevity. Further, present evidence suggests that environmental and lifestyle factors are by far the greatest determinant of variations in human longevity; the search for mechanisms of longevity arising from genetic variants within our species will likely produce little of value.

Recent studies suggested that noncoding RNAs are involved in healthy aging and/or age-related diseases. It remains, however, largely unknown whether circular RNAs (circRNAs), a class of endogenous noncoding RNA with a covalently closed continuous loop predominantly generated from back-splicedback-spliced exons, and acting as 'microRNA sponges' or 'scaffolding' for RNA-binding protein, in human longevity. Increasing evidence has revealed the crucial roles of circRNAs in multiple biological processes and even in human diseases. For instance, several circRNAs were related with age-related diseases, including neurodegenerative diseases, cardiovascular diseases, type 2 diabetes, and, even, cancers. Nevertheless, their roles in the process of human lifespan extension are largely unexplored.

In this study, we investigated the circRNAs expression pattern of longevous families, from a Chinese cohort of longevity. Based on weighted circRNA co-expression network analysis, we found that longevous elders (98.3 ± 3.4 years) specifically gained eight but lost seven conserved circRNA-circRNA co-expression modules compared with normal elder controls (spouses of offspring of long-lived individuals, age = 59.3 ± 5.8 years). Both the gained and lost module-related genes were enriched in infectious disease-related pathways. This suggests that these elders might have a history of infection, which could be related to life in the early and middle twentieth century when medical health care was poorer and contagious diseases were prevalent. It seems that these circRNAs may be associated with previous responses to infectious diseases.

Given that these modules, as predicted by mRNA-circRNA co-expression analysis, were closely related to processes involved in lifespan extension, the gain and loss of these circRNA-circRNA co-expression modules in very long-lived individuals are unlikely to be a random process but rather contribute to healthy human aging and may represent a new target for the regulation of healthy human aging.

Link: https://doi.org/10.3390/genes13050749

Metabolic activity slows down in late life, perhaps in large part because this reduces the risk of cancer. In an environment of pervasive molecular damage, a growing burden of nuclear DNA mutations, inflammation, and a declining immune system, more cellular replication and activity implies an ever greater risk of cancer. Longevity in our species appears to be a trade-off that selects for a slow decline in tissue function coupled to a lower cancer risk, rather than maintained tissue function coupled to a higher cancer risk.

Greater human longevity relative to other primates is a comparatively recent development in evolutionary history, likely the result of our greater intelligence and capacity for culture. When older people can significantly influence the reproductive success of their grandchildren, there is a selection pressure for longer lives. This view of exceptional human longevity is called the grandmother hypothesis, and may also explain some other aspects of human physiology and aging that are unusual among mammals, such as the existence of menopause.

We should expect to see signs of slowed metabolic activity wherever we look in human cellular biochemistry and cell behavior. For example, stem cell activity declines in response to the aged tissue environment; fewer daughter somatic cells are generated to replace those that should turn over. Cell division rates decline in general, and cells spend longer in their tissue before reaching the Hayflick limit. As today's open access paper notes, the synthesis and turnover of proteins in cells may also exhibit a slowdown in at least some cell types. These slowdowns have consequences. We can consider that cells and proteins are likely to accumulate more stochastic damage and exhibit more dysfunction in many ways, for example, given longer working lifetimes.

Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration

Analysis of brain protein levels in physiologically aged brain has revealed only minor alterations in protein abundances in the aged adult versus the young adult brain, reflecting differences in inflammation-related proteins or changes in proteasome and ribosome stoichiometry. This indicates that protein turnover, which regulates the equilibrium between protein synthesis and degradation, might be especially affected in aging and could lead to changes preluding neuropathology. Protein synthesis has been historically described as declining with age, although not all studies agree and often point to high organ and tissue variability. Protein degradation is also commonly described as compromised in aging. If both synthesis and degradation decline, lifetimes should increase and general turnover of proteins should be slower, possibly favoring the collapse of proteostasis networks and initiating the accumulation of potentially toxic proteins. While this general trend would explain the malfunctioning of macromolecules, protein turnover in different tissues has shown little or no overall changes in aged animals versus younger controls.

While results in invertebrate models suggest that proteostasis is essential for the survival of aging neurons, and that there is an age-related decline in protein turnover rates, in the aged mammalian brain an extensive quantitative analysis of protein turnover is currently lacking. Our group has introduced an experimental workflow for the global quantification of protein lifetimes. Here, using this workflow, we obtained protein lifetimes in the aged brain cortex, in cerebellum, and in their synaptic fractions, aiming to provide cellular and subcellular information about changes in brain protein stability. We then compared protein lifetimes between young adult and aged mice addressing the changes observed during aging. We analyzed our results extensively with bioinformatics and revealed that the proteome in the aged brain is turned over at a slower rate (~20%). In addition, aging establishes an intrinsic alteration of the proteostasis network that specifically preserves proteins with high biosynthetic cost.

People exhibiting chronic disease in middle age, such as type 2 diabetes or other lifestyle conditions brought on being overweight and sedentary, have a greater risk of dementia in later life. A sizable amount of evidence exists to support this relationship, and the point is once again illustrated by the data presented in this open access paper. Maintaining good health has a great deal of value, especially in an era of progress towards therapies to slow and reverse aspects of aging. Being in better health in late life will mean a greater ability to take advantage of therapies that will further improve and lengthen healthy life span.

A further consequence of population ageing is the increase in multimorbidity, conventionally defined as the presence of two or more chronic diseases irrespective of the severity of such conditions. Recent estimates suggest that more than 50% of older adults in high income countries report multiple chronic conditions, although multimorbidity is not confined to older adults. The development of chronic diseases at younger ages has implications for their management, the risk of premature mortality, and the cost of care. Multimorbidity is estimated to have an adverse effect on patients' outcomes and healthcare systems that is greater than that of chronic conditions considered indivdually.

In older adults with dementia, the presence of several comorbid conditions is common. A recent study of older adults (mean age 75 years) followed for a mean of 8.4 years reported higher risk of dementia in those with multimorbidity, but studies that have followed individuals for longer are lacking. Recent studies also suggest that the risk of dementia is higher in people with cardiometabolic disease in midlife rather than late life, suggesting that age at onset of multimorbidity is an important determinant of risk of dementia.

Accordingly, we examined whether longer duration of multimorbidity and severity of multimorbidity (defined as three or more chronic conditions), implying earlier age at onset of multimorbidity, increase the risk of dementia at older ages in the Whitehall II cohort study spanning 30 years. The prevalence of multimorbidity (≥2 chronic diseases) was 6.6% (655/9937) at age 55 and 31.7% (2464/7783) at age 70; 639 cases of incident dementia occurred over a median follow-up of 31.7 years. After adjustment for sociodemographic factors and health behaviours, multimorbidity at age 55 was associated with subsequent risk of dementia, hazard ratio 2.44. Multimorbidity, particularly when onset is in midlife rather than late life, has a robust association with subsequent dementia. The increasingly younger age at onset of multimorbidity makes prevention of multimorbidity in people with a first chronic disease important.

Link: https://doi.org/10.1136/bmj-2021-068005

Researchers here show that intermittent methionine restriction (four days off, three days on, alternating) produces the same metabolic benefits as continuous methionine restriction, though to a lesser degree. Methionine sensing is one of the major mechanisms by which cells respond to low calorie intake, so it is possible to trigger this response without reduced calorie intake by reducing only levels of the essential amino acid methionine in the diet. To my eyes, the most interesting outcome here is that there is a large difference in metrics between the groups placed on a zero methionine diet for three days versus those placed on a low methionine diet for three days.

From a practical point of view, the difficulty in practicing methionine restriction lies in organizing the diet, as near all staple foods contain a lot of methionine. Thus intermittent methionine restriction is going to be just as challenging as methionine restriction: it would require about the same amount of work to adopt this lifestyle choice either way. Further, any period of complete methionine restriction would require a manufactured diet. Those medical diet products exist, but are very expensive and/or not available to the public at large.

A sustained state of methionine restriction (MR) dramatically extends the healthspan of several model organisms. For example, continuously methionine-restricted rodents have less age-related pathology and are up to 45% longer-lived than controls. Promisingly, MR is feasible for humans, and studies have suggested that methionine-restricted individuals may receive similar benefits to rodents. However, long-term adherence to a methionine-restricted diet is likely to be challenging for many individuals. Prompted by this, and the fact that intermittent variants of other healthspan-extending interventions (i.e., intermittent fasting and the cyclic ketogenic diet) are just as effective, if not more, than their continuous counterparts, we hypothesized that an intermittent form of MR might produce similar healthspan benefits to continuous MR.

Accordingly, we developed two increasingly stringent forms of intermittent MR (IMR) and assessed whether mice maintained on these diets demonstrate the beneficial metabolic changes typically observed for continuous MR. To the best of our knowledge, we show for the first time that IMR produces similar beneficial metabolic effects to continuous MR, including improved glucose homeostasis and protection against diet-induced obesity and hepatosteatosis. In addition, like continuous MR, IMR confers beneficial changes in the plasma levels of the hormones IGF-1, FGF-21, leptin, and adiponectin. Together, our findings demonstrate that the more practicable intermittent form of MR produces similar healthspan benefits to continuous MR, and thus may represent a more appealing alternative to the classical intervention.

Link: https://doi.org/10.1111/acel.13629

Epigenetic clocks to assess age are constructed via the application of machine learning to epigenetic data at various ages, examining which CpG sites are methylated and which are not, and identifying weighted combinations of specific sites that correlate well with chronological age. Researchers have shown that an epigenetic age greater than chronological age, known as epigenetic age acceleration, correlates with greater mortality and burden of age-related disease. It is therefore thought that epigenetic clocks may allow for the rapid assessment of potential rejuvenation therapies, an important goal for the research and development community.

At present it is slow and expensive to quantify the degree to which any given approach to the treatment of aging is actually useful in mice, and very much more challenging in human patients, given the need for long-term studies. The ability to run a quick, low-cost assay immediately before and immediately after treatment, to obtain an accurate assessment of biological age, would greatly speed up development, allowing the research community to focus more rapidly on approaches that work, versus those that are marginal.

Unfortunately, there is as yet little understanding of what exactly is being measured by epigenetic clocks. How does the methylation of specific CpG sites relate to the underlying mechanisms of aging, or specific consequences of those mechanisms? That is a black box, and clocks likely reflect only some of the mechanisms and changes of aging. Without knowing which aspects of aging determine epigenetic age for any given epigenetic clock, the only way to trust that the clock will usefully measure the effects of a potential rejuvenation therapy is to calibrate it against that therapy in long-term studies. Which rather defeats the point, as then we are right back to the slow and untenable present situation.

Today's interesting open access paper is an example of the way in which researchers are starting to make inroads into understanding how specific aspects of aging relate to epigenetic age in various clocks. The authors here picked one clock and performed a variety of in vitro studies on cells in an attempt to illuminate the relationships between age-related damage and change in function and the epigenetic age as assessed by the chosen clock. The data and conclusions are interesting, but it is worth bearing in mind that this is just a first step on a likely lengthy road.

The relationship between epigenetic age and the hallmarks of ageing in human cells

The excitement following the development of epigenetic clocks has been tinged with uncertainty as to the meaning of their measurements (i.e., epigenetic age, EpiAge). This uncertainty is compounded by the fact that different epigenetic clocks appear to measure different features of aging. Our investigations using the Skin&blood clock uncovered many features of epigenetic aging, of which two are particularly important. First, epigenetic aging initiates at very early point of life when pluripotency ceases. This process evidently continues through development, postnatal growth, maturity, and adulthood until death, as epigenetic clocks are applicable to the entire lifespan. Therefore, epigenetic aging is not an auxiliary phenomenon but an integral part of the deterministic process of life. Despite this fact, epigenetic aging is not refractive to the influence of external factors that can alter its rate. Indeed, experiments demonstrate the malleability of the rate of epigenetic aging.

At a higher level of consideration, the innate nature and inevitability of epigenetic aging contrasts with the stochasticity of wear and tear, which is presumed to exert a measurable aging effect only later in life when damage outstrips repair. This, however, does not argue against the relevance of wear and tear and cellular senescence. Instead, these distinct stochastic processes are likely to synergize with epigenetic aging in manifesting the overall phenotypical features of aging. If a successful strategy against aging is to be found, then these distinct and parallel aging mechanisms must be addressed; for example, by the removal of senescent cells, together with the retardation of epigenetic aging.

Another pivotal point concerns the ticking of the clock. It is intuitive to assume that this ticking is owed to dynamic changes of methylation on age-related CpGs in all cells in a tissue. Our observations with cell clones suggest that the ticking of the epigenetic clock is, at the very least, a measure of change in cell composition with age. This change can perceivably occur through expansion or reduction of a subpopulation of cells with different ages within the tissue. It was previously shown that mouse muscle stem cells are considerably younger. Therefore, such changes can conceivably result from alterations in the relative amounts of stem cells and non-stem cells, although the impact of stem cells from many more different tissues to aging requires further empirical investigations.

It was particularly important to address the question of the relationship between epigenetic aging and cellular senescence, as previous reports were equivocal in their conclusions. Here, using primary cells from many individual donors, the results are clear that cellular senescence, although undoubtedly a major contributor to the aging phenotype, is not associated with epigenetic aging, as measured by the Skin&blood clock. Similarly, DNA damage, and genomic instability have been hypothesized and proffered as means by which cells undergo epigenetic aging. Here, using different primary cell types derived from multiple donors, irradiated in different ways (acute or continuous) at different doses and dose rates, we did not observe any measurable impact on the rate of epigenetic aging.

Collectively, the results described here with primary cells from a large number of donors and multiple cell types, as well as in vivo mouse experiments previously reported, indicate that nutrient sensing, mitochondrial function, stem cell exhaustion, and altered cell-cell communication affect epigenetic aging as measured by Skin&blood clock, but cellular senescence, telomere attrition, and genomic instability do not. The connection of epigenetic aging to four of the hallmarks of aging implies that these hallmarks are also mutually connected at a deeper level. If so, epigenetic clocks will be instrumental in identifying the underlying unifying mechanisms. The absence of a connection between the other aging hallmarks and epigenetic aging suggests that aging is a consequence of multiparallel mechanisms, crudely divided into deterministic pathways: those associated with epigenetic aging and stochastic ones, which are independent of epigenetic aging and may result instead from wear and tear.

A growing body of evidence points towards the importance of inflammation in brain tissue, and chronic inflammation in general, to the development of neurodegenerative conditions. Chronic inflammation is disruptive of tissue function wherever it occurs in the body. This sustained, unresolved inflammation is one of the more important ways in which the accumulation of senescent cells cause harm in later life. With the discovery of senolytic therapies to clear senescent cells, and a mapping of the inflammatory signals secreted by senescent cells, increasing attention has been given to the role of inflammation in many conditions.

Beyond the removal of senescent cells, other approaches to the reduction of inflammation remain problematic. They largely take the form of interference in signaling that is needed for both excessive, unresolved inflammation and necessary, short-term inflammation. These therapies thus degrade essential functions of the immune system as an unwanted side-effect. Better means of suppressing unresolved inflammation are much needed.

Converging evidence from both genetically at-risk cohorts and clinically normal older individuals suggests that the pathogenesis of Alzheimer's disease (AD) begins years before the clinical diagnosis of dementia is established. Over time, the definition of AD has changed from a traditionally symptom-based disease entity to a clinico-biological construct encompassing a 15-20 year preclinical phase, a 3-6 year prodromal period and a terminal dementia stage.

In addition to deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, neuroinflammation has been identified as the third core characteristic crucial in the pathogenesis of AD. Accumulating evidence suggests that neuroinflammation, as well as activation of microglia and astrocytes, plays an important role in AD pathogenesis. Although whether or not inflammation itself is an initiator or consequence of the disease process, its importance in AD is undeniable.

Targeting of neuroinflammation is potentially an extremely effective strategy for AD prevention and therapy during the preclinical stage prior to the occurrence of significant neuronal loss. Several phase I/II clinical trials evaluating the targeting of TNF-α, TREM2, or CD33 have shown promising results. As reported data remain controversial, and most of the AD clinical trials - including those investigating anti-inflammatory compounds - failed, longitudinal studies enrolling large cohorts of participants with accurate clinical and biomarker-based characterizations are needed to identify potentially effective anti-inflammatory targets and drugs relevant to AD therapy.

Link: https://doi.org/10.2147/CIA.S357558

Given the growing evidence for inflammatory and senescent microglia and astrocytes to drive the progression of neurodegenerative conditions such as Alzheimer's disease, there is a need for practical, cost-effective ways to assess the burden of inflamed supporting cells in the brain. The senolytic combination of dasatinib and quercetin has been shown to clear senescent cells in the brain, and improve symptoms in animal models of neurodegeneration. Similarly, CSF1R inhibitors such as PLX3397 can clear microglia from the brain, a beneficial procedure when performed in mice with neuroinflammation. Trials in human patients will be that much easier to justify to the powers that be given a way to clearly assess the degree to which harmful cells are cleared by such treatments.

Researchers have demonstrated that diffusion-weighted MRI (dw-MRI) can noninvasively and differentially detect the activation of microglia and astrocytes, two types of brain cells that are at the basis of neuroinflammation and its progression. Degenerative brain diseases such as Alzheimer's and other dementias, Parkinson's, or multiple sclerosis are a pressing and difficult problem to address. Sustained activation of two types of brain cells, microglia and astrocytes leads to chronic inflammation in the brain that is one of the causes of neurodegeneration and contributes to its progression.

This is the first time it has been shown that the signal from this type of MRI can detect microglial and astrocyte activation, with specific footprints for each cell population. The researchers have also shown that this technique is sensitive and specific for detecting inflammation with and without neurodegeneration, so that both conditions can be differentiated. In addition, it makes it possible to discriminate between inflammation and demyelination characteristic of multiple sclerosis.

To validate the model, the researchers used an established paradigm of inflammation in rats based on intracerebral administration of lipopolysaccharide (LPS). In this paradigm, neuronal viability and morphology are preserved, while inducing, first, an activation of microglia, and in a delayed manner, an astrocyte response. This temporal sequence of cellular events allows glial responses to be transiently dissociated from neuronal degeneration and the signature of reactive microglia investigated independently of astrogliosis. To isolate the imprint of astrocyte activation, the researchers repeated the experiment by pretreating the animals with an inhibitor that temporarily ablates about 90% of microglia.

Link: https://www.eurekalert.org/news-releases/954018

The metabolic dysfunction of type 2 diabetes is known to accelerate the pathologies of aging. A range of mechanisms are involved, the most prominent of which is elevated chronic inflammation. Type 2 diabetes is a lifestyle condition caused, in the vast majority of cases, by being very overweight. Excess visceral fat tissue, required to produce the metabolic syndrome that leads into type 2 diabetes, accelerates the production of pro-inflammatory and generally disruptive senescent cells, but also produces inflammation via other mechanisms, such as the release of DNA debris from dying fat cells. Diabetes also features increased levels of circulating advanced glycation end-products (AGEs), and this sugary metabolic waste provokes inflammatory behavior via the receptor for AGEs (RAGE).

Neurodegenerative conditions are also driven and characterized by chronic inflammation. It might be expected that years of raised chronic inflammation due to excess fat tissue and an aberrant diabetic metabolism will act to accelerate neurodegeneration, just as it does for all of the other common age-related conditions. The mechanisms involved may be direct, such as a disruption of the supporting immune cells in the brain via inflammatory signaling, as activated and senescent microglia are implicated in the progression of conditions such as Alzheimer's disease. It may be more indirect, involving accelerated cardiovascular aging (hypertension, atherosclerosis, blood-brain barrier dysfunction, reduced capillary density, and so forth) that produces harmful outcomes that contribute to neurodegeneration, such as a reduced blood supply and increased rupture of small blood vessels in brain tissue.

Type 2 diabetes accelerates brain aging and cognitive decline

Scientists have demonstrated that normal brain aging is accelerated by approximately 26% in people with progressive type 2 diabetes compared with individuals without the disease. The results further suggest that by the time type 2 diabetes is formally diagnosed, there may already be significant structural damage to the brain. There is already strong evidence linking type 2 diabetes with cognitive decline, yet few patients currently undergo a comprehensive cognitive assessment as part of their clinical care. It can be difficult to distinguish between normal brain aging that begins in middle age, and brain aging caused or accelerated by diabetes.

The team made use of the largest available brain structure and function dataset across human lifespan: UK Biobank data from 20,000 people aged 50 to 80 years old. This dataset includes brain scans and brain function measurements and holds data for both healthy individuals and those with a type 2 diabetes diagnosis. They used this to determine which brain and cognitive changes are specific to diabetes, rather than just aging, and then confirmed these results by comparing them with a meta-analysis of nearly 100 other studies.

Type 2 diabetes mellitus accelerates brain aging and cognitive decline: Complementary findings from UK Biobank and meta-analyses

We characterized neurocognitive effects independently associated with T2DM and age in a large cohort of human subjects from the UK Biobank with cross-sectional neuroimaging and cognitive data. We then proceeded to evaluate the extent of overlap between the effects related to T2DM and age by applying correlation measures to the separately characterized neurocognitive changes. Our findings were complemented by meta-analyses of published reports with cognitive or neuroimaging measures for T2DM and healthy controls (HCs).

T2DM was associated with marked cognitive deficits, particularly in executive functioning and processing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy. The structural and functional changes associated with T2DM show marked overlap with the effects correlating with age but appear earlier, with disease duration linked to more severe neurodegeneration. The neurocognitive impact of T2DM suggests marked acceleration of normal brain aging. T2DM gray matter atrophy occurred approximately 26% ± 14% faster than seen with normal aging.

SGLT2 inhibitors are used to treat type 2 diabetes. As is the case for a number of such medications, there is some evidence for them to be beneficial for aged people without this condition. In this example, researchers demonstrate improvements vascular function in aged mice that are treated with one of the approved SGLT2 inhibitors. They also note a range of other evidence for cardiovascular benefits to result from this class of intervention. It remains a question as to which of the possible underlying mechanisms are the important ones, but treatment does seem to reduce blood pressure and arterial stiffness, both of which are significant contributors to late life mortality in our species.

Therapeutic strategies such as lifestyle modifications (weight loss and increased physical activity), antihypertensive therapy, and lipid-lowering medications have shown variable effectiveness at improving endothelial function and ameliorating arterial stiffening and remodeling in older adults. Thus, additional therapeutic approaches aimed at improving vascular health in older individuals are needed. In this regard, evidence from different clinical trials demonstrates that inhibition of SGLT2 results in decreased cardiovascular events and cardiovascular disease related mortality in both patients with and without diabetes. SGLT2 co-transporters are predominantly located in the proximal renal tubules and are responsible for reabsorption of 90% of the glucose in the glomerular filtrate. Indeed, while SGLT2 inhibitors were originally designed as glucose lowering agents, growing evidence supports their beneficial, non-glucose lowering dependent, renal, and cardiovascular effects. In particular, the SGLT2 inhibitor empagliflozin (Empa) has been shown to reduce cardiovascular mortality and nonfatal myocardial infarction, stroke, and cardiovascular death regardless of the presence of type 2 diabetes.

Mechanisms postulated to explain the beneficial cardiovascular properties of SGLT2 inhibition include weight loss and antihypertensive effect, diuresis-induced blood volume reduction, increased red blood cell mass, improved myocardial bioenergetics, decreased arterial stiffness, and improved endothelial function. However, the extent to which the favorable cardiovascular effects of SGLT2 inhibitors are translatable to aging remains unknown. Given the above, the potential impact of SGLT2 inhibition on aging-related endothelial dysfunction, arterial stiffening, and remodeling warrants investigation.

Herein, we first confirmed in a cohort of adult human subjects that aging is associated with impaired endothelial function and increased arterial stiffness and that these two variables are inversely correlated. Next, we investigated whether treatment with the SGLT2 inhibitor, Empa, for 6 weeks ameliorates endothelial dysfunction and reduces arterial stiffness in aged mice with confirmed vascular dysfunction. We report that Empa-treated mice exhibited improved mesenteric endothelial function compared with control, in parallel with reduced mesenteric artery and aortic stiffness. Our findings demonstrate that Empa improves endothelial function and reduces arterial stiffness in a preclinical model of aging, making SGLT2 inhibition a potential therapeutic alternative to reduce the progression of cardiovascular disease in older individuals.

Link: https://doi.org/10.1007/s11357-022-00563-x

Some of the many longevity-enhancing mutations in nematode worms discovered over the past 30 years involve a mild impairment of mitochondrial function. Researchers here show that the chain of cause and consequence leading from such impairment through to improved cell and tissue function requires the operation of the thioredoxin system in mitochondria, responsible for clearing out excessive oxidizing molecules. Mitochondria produce oxidants as a consequence of their operation, and a mild increase can result in upregulation of cellular maintenance processes in response, producing a net gain in cell function. Thioredoxin may here be ensuring that the increase in oxidants produced by impaired mitochondria is modest enough for that outcome, rather than being large enough to tip over into a net negative effect on cell function.

Mild impairment of mitochondrial function has been shown to increase lifespan in genetic model organisms including worms, flies and mice. To better understand the mechanisms involved, we analyzed RNA sequencing data and found that genes involved in the mitochondrial thioredoxin system, trx-2 and trxr-2, are specifically upregulated in long-lived mitochondrial mutants but not other non-mitochondrial, long-lived mutants. Upregulation of trx-2 and trxr-2 is mediated by activation of the mitochondrial unfolded protein response (mitoUPR). While we decided to focus on the genes of the mitochondrial thioredoxin system for this paper, we identified multiple other antioxidant genes that are upregulated by the mitoUPR in the long-lived mitochondrial mutants including sod-3, prdx-3, gpx-6, gpx-7, gpx-8, and glrx-5.

In exploring the role of the mitochondrial thioredoxin system in the long-lived mitochondrial mutants, nuo-6 and isp-1, we found that disruption of either trx-2 or trxr-2 significantly decreases their long lifespan, but has no effect on wild-type lifespan, indicating that the mitochondrial thioredoxin system is specifically required for their longevity. In contrast, disruption of the cytoplasmic thioredoxin gene trx-1 decreases lifespan in nuo-6, isp-1, and wild-type worms, indicating a non-specific detrimental effect on longevity. Disruption of trx-2 or trxr-2 also decreases the enhanced resistance to stress in nuo-6 and isp-1 worms, indicating a role for the mitochondrial thioredoxin system in protecting against exogenous stressors. Overall, this work demonstrates an important role for the mitochondrial thioredoxin system in both stress resistance and lifespan resulting from mild impairment of mitochondrial function.

Link: https://doi.org/10.1016/j.redox.2022.102335