Fight Aging!

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Contents

• Aging is Complex and Shifts Dramatically Over Late Life as it Accelerates
• How One Type of Tumor Converts Innate Immune Cells to its Cause
• Centenarians Better Regulate the Chronic Inflammation of Aging
• Longevity Conferences Coming up in Late 2022
• Senescent Vascular Smooth Muscle Cells in Atherosclerosis
• TDP-43 Aggregation is Present in Many Older People, Overlapping with Alzheimer's Pathology
• Neuroinflammation as a Link Between Atherosclerosis and Neurodegenerative Conditions
• DDIT4 and HDAC4 Overexpression Reduces Harmful Signaling of Senescent Cells in Aged Tissues
• Inflammatory Microglia in the Brain as a Contribution to Cardiovascular Disease
• The Astrocyte Urea Cycle in Alzheimer's Disease
• Cellular Senescence in the Midbrain in the Development of Parkinson's Disease
• Negligible Senescence in a Number of Reptilian and Amphibian Species
• Excess Tau Protein Interferes in Signaling Between Neurons
• Delivery of VEGF-A in Aged Skin as an Approach to Improve Function
• Influenza Vaccination Associated with a 40% Reduced Risk of Alzheimer's Disease

Aging is Complex and Shifts Dramatically Over Late Life as it Accelerates
https://www.fightaging.org/archives/2022/06/aging-is-complex-and-shifts-dramatically-over-late-life-as-it-accelerates/

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.

How One Type of Tumor Converts Innate Immune Cells to its Cause
https://www.fightaging.org/archives/2022/06/how-one-type-of-tumor-converts-innate-immune-cells-to-its-cause/

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.

Centenarians Better Regulate the Chronic Inflammation of Aging
https://www.fightaging.org/archives/2022/06/centenarians-better-regulate-the-chronic-inflammation-of-aging/

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.

Longevity Conferences Coming up in Late 2022
https://www.fightaging.org/archives/2022/06/longevity-conferences-coming-up-in-late-2022/

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.

Senescent Vascular Smooth Muscle Cells in Atherosclerosis
https://www.fightaging.org/archives/2022/07/senescent-vascular-smooth-muscle-cells-in-atherosclerosis/

Senescent cells serve many purposes in the body, such as aiding in wound healing and suppression of cancer, but they become harmful when present in significant numbers for an extended period of time. This occurs with age, as the immune system becomes less effective at its task of clearing those senescent cells that fail to undergo programmed cell death. As senescent cells are created constantly, when somatic cells hit the Hayflick limit on replication, and to a lesser degree in response to molecular damage, a slowing of clearance leads to an accumulation of these errant cells. Senescent cells secrete a mix of signals, the senescence-associated secretory phenotype (SASP), that, when present over the long term, provokes harmful inflammation, restructuring of the extracellular matrix, and detrimental changes in cell behavior.

Atherosclerosis is an inflammatory condition, in which fatty deposits form in artery walls due to the dysfunction of the macrophage cells responsible for removing that damage. More inflammatory signaling makes matters worse, by both changing the behavior of macrophages, and calling in more macrophages to swell the mass of the atherosclerotic plaque. That is enough on its own to consider targeting senescent cells for destruction, to remove their inflammatory signaling as a way to slow the growth of plaque. Today's open access paper adds a few other concerns, such as the way in which senescent cells may be disruptive of the protective fibrosis that helps stabilize soft plaques.

There is good reason to think that senolytic therapies to selectively destroy senescent cells may be beneficial in the context of atherosclerosis, or indeed in any age-related condition with a strong connection to chronic inflammation, but not all senolytics may effectively target the relevant senescent populations, or localize sufficiently to the arteries, as noted in the paper here. The question of whether senescent cells provide a major contribution or a minor contribution to the progression of atherosclerosis remains open, though the early attempts to produce benefits in animal models have not been promising. If that state of affairs continue, then attention must return to other pathological mechanisms.

Senescence in Vascular Smooth Muscle Cells and Atherosclerosis

Vascular smooth muscle cells (VSMCs) are the primary cell type involved in the atherosclerosis process; senescent VSMCs are observed in both aged vessels and atherosclerotic plaques. Cellular senescence is not a static cellular state, but a dynamic process during which cells undergo quiescence (initial transient senescence), early senescence (stable growth arrest), complete senescence (chromatin changes associated with senescence and SASP), and late/deep senescence (phenotypic diversification). Similar to other cell types, senescent VSMCs have impaired proliferative potential coupled with increased propensity for expression of cellular senescence markers and cell death.

VSMCs aging is characterized by a shift from a contractile phenotype to a synthetic phenotype, impaired response to contractile or diastolic mediators secreted by endothelial cells, and changes in ion channel expression and abundance in the cell membrane. In atherosclerosis, senescent VSMCs may be present only in the intima rather than the mesenchyme, and VSMCs senescence is associated primarily with plaque size rather than plaque formation. Advanced atherosclerotic plaques are covered by fibrous caps containing VSMCs and extracellular matrix (ECM) molecules. Given that VSMCs can secrete and deposit ECM proteins, they are generally considered to be protective against atherosclerotic plaque instability. However, senescent VSMCs promote plaque vulnerability by secreting matrix-degrading proteases. Compared with normal VSMCs, collagen secretion from senescent VSMCs is reduced which further impairs plaque stability. Thus, senescent VSMCs not only accumulate in the atherosclerotic setting, but their properties exacerbate the development of atherosclerosis and increase the risk of atherosclerosis-related complications.

It is unclear whether senolytic drugs prevent atherosclerosis through multiple mechanisms or whether they do so only by clearing senescent cells. Not all anti-aging drugs are effective against atherosclerosis; long-term oral administration of dasatinib + quercetin (D + Q) significantly reduced aortic medial senescent cell markers in chronic hypercholesterolemic mice and naturally aging mice, as well as improving vasomotor function, but the mice still developed atherosclerosis. Further, the size of atherosclerotic plaques did not decrease following these treatments.

TDP-43 Aggregation is Present in Many Older People, Overlapping with Alzheimer's Pathology
https://www.fightaging.org/archives/2022/06/tdp-43-aggregation-is-present-in-many-older-people-overlapping-with-alzheimers-pathology/

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).

Neuroinflammation as a Link Between Atherosclerosis and Neurodegenerative Conditions
https://www.fightaging.org/archives/2022/06/neuroinflammation-as-a-link-between-atherosclerosis-and-neurodegenerative-conditions/

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.

DDIT4 and HDAC4 Overexpression Reduces Harmful Signaling of Senescent Cells in Aged Tissues
https://www.fightaging.org/archives/2022/06/ddit4-and-hdac4-overexpression-reduces-harmful-signaling-of-senescent-cells-in-aged-tissues/

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.

Inflammatory Microglia in the Brain as a Contribution to Cardiovascular Disease
https://www.fightaging.org/archives/2022/06/inflammatory-microglia-in-the-brain-as-a-contribution-to-cardiovascular-disease/

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.

The Astrocyte Urea Cycle in Alzheimer's Disease
https://www.fightaging.org/archives/2022/06/the-astrocyte-urea-cycle-in-alzheimers-disease/

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."

Cellular Senescence in the Midbrain in the Development of Parkinson's Disease
https://www.fightaging.org/archives/2022/06/cellular-senescence-in-the-midbrain-in-the-development-of-parkinsons-disease/

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.

Negligible Senescence in a Number of Reptilian and Amphibian Species
https://www.fightaging.org/archives/2022/06/negligible-senescence-in-a-number-of-reptilian-and-amphibian-species/

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."

Excess Tau Protein Interferes in Signaling Between Neurons
https://www.fightaging.org/archives/2022/06/excess-tau-protein-interferes-in-signaling-between-neurons/

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.

Delivery of VEGF-A in Aged Skin as an Approach to Improve Function
https://www.fightaging.org/archives/2022/07/delivery-of-vegf-a-in-aged-skin-as-an-approach-to-improve-function/

Researchers here report on an investigation of mechanisms by which aged human skin is improved in function when transplanted onto young immunocompromised mice. They identified VEGF-A as a factor involved in this improvement, and showed that delivering VEGF-A to human skin models can reduce signatures of aging. This is interesting, as a number of skin conditions exhibit high levels of VEGF-A, and are treated by therapies that are shown to inhibit VEGF-A in addition to other effects. Thus more work is needed here in order to understand whether or not VEGF-A based treatments are a viable path to improving aged skin function.

Human skin is ideally suited as a preclinical aging research model but is rarely used by mainstream aging research for this purpose. Yet, aging of the human body becomes nowhere sooner and more immediately visible than in skin changes and hair graying. While massive industry efforts therefore cater to the ancient human desire to halt or reverse the phenotype of aging skin, success at this frontier has remained moderate at best, and many product claims of in vivo rejuvenation of human skin are typically insufficiently substantiated. Nevertheless, the molecular mechanisms that underlie extrinsic and intrinsic skin aging in vivo are becoming increasingly understood, albeit mostly in nonhuman animal models of uncertain clinical relevance.

Previously, we had shown that grafting aged human skin to immunocompromised young mice reverts several aging-associated parameters in the epidermis of the human xenotransplants. Yet, it is unknown whether the observed skin rejuvenation effects extend beyond the epidermis, and the molecular mechanisms that underlie this striking epidermal rejuvenation phenomenon have remained elusive. Examining this accessible, experimentally pliable, and clinically relevant model for human organ rejuvenation in vivo, the present study hoped to identify druggable targets for human organ rejuvenation.

Transplanting aged human skin onto young immunocompromised mice morphologically rejuvenates the xenotransplants. This is accompanied by angiogenesis, epidermal repigmentation, and substantial improvements in key aging-associated biomarkers, including ß-galactosidase, p16ink4a, SIRT1, PGC1α, collagen 17A, and MMP1. Angiogenesis- and hypoxia-related pathways, namely, vascular endothelial growth factor A (VEGF-A) and HIF1A, are most up-regulated in rejuvenated human skin. This rejuvenation cascade, which can be prevented by VEGF-A-neutralizing antibodies, appears to be initiated by murine VEGF-A, which then up-regulates VEGF-A expression/secretion within aged human skin.

While intradermally injected VEGF-loaded nanoparticles suffice to induce a molecular rejuvenation signature in aged human skin transplanted onto old mice, VEGF-A treatment improves key aging parameters also in isolated, organ-cultured aged human skin, i.e., in the absence of functional skin vasculature, neural, or murine host inputs. This identifies VEGF-A as the first pharmacologically pliable master pathway for human organ rejuvenation in vivo and demonstrates the potential of our humanized mouse model for clinically relevant aging research.

Influenza Vaccination Associated with a 40% Reduced Risk of Alzheimer's Disease
https://www.fightaging.org/archives/2022/07/influenza-vaccination-associated-with-a-40-reduced-risk-of-alzheimers-disease/

Researchers here note a sizable reduction in Alzheimer's disease risk in that part of the aged population that receives influenza vaccines. There is the usual question as to whether vaccination is a proxy for conscientiousness in health matters throughout later life, but here the focus is on biological mechanisms that might explain the effect. The most plausible to my eyes is the phenomenon of trained immunity, in which vaccination for a specific pathogen can provoke a general improvement in all functions of the innate immune system. This improvement includes reduced inflammation, and the chronic inflammation of aging is clearly important in the onset and progression of neurodegenerative conditions.

This retrospective cohort study revealed that in adults aged 65 or old without dementia, mild cognitive impairment, or encephalopathy, patients who received at least one influenza vaccine were 40% less likely than their non-vaccinated peers to develop incident Alzheimer's disease (AD) during the 4-year follow-up period. The mechanisms underlying the apparent protective effects of influenza vaccination on AD risk merit further investigation. These mechanisms - and those underlying the effects of adulthood vaccinations on all-cause dementia risk in general - can be grouped into at least three broad, non-exclusive categories: 1) influenza-specific mechanisms, including mitigation of damage secondary to influenza infection and/or epitopic similarity between influenza proteins and AD pathology; 2) non-influenza-specific training of the innate immune system; and 3) non-influenza-specific changes in adaptive immunity via lymphocyte-mediated cross-reactivity.

The apparent effect of influenza vaccination on AD risk may be secondary to influenza-specific immunity conferred by the vaccine. Central nervous system (CNS) injury during influenza infection can occur from direct viral invasion of nervous tissues or as collateral damage from the systemic immune response to peripheral infection. An association between flu infection and AD risk is supported by mouse studies demonstrating that peripheral infection of wild-type mice with non-neurotropic influenza strains induces excessive microglial activation and subsequent alteration of neuronal morphology, particularly in the hippocampus, that persists after infection resolution.

Long-term, non-influenza-specific alteration of the innate immune system presents another class of mechanisms potentially underlying influenza vaccination's apparent effect on AD risk. Several vaccines, including the influenza vaccine, are associated with non-specific protective effects via long-term reprogramming of innate immune cells, a process termed "trained immunity". Several studies have shown that the innate-related changes in peripheral cytokines associated with vaccination can directly affect microglial activity, including the efficiency of microglia in clearing amyloid-β aggregates. Another mechanism related to innate immunity that potentially underlies the association between flu vaccination and AD is alteration of the sustained low-grade systemic elevation of proinflammatory cytokines referred to as "inflammaging" that is commonly observed among older adults.