Fight Aging!

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Contents

• Periodic Reprogramming via Gene Therapy Doubles Remaining Life Span in Old Mice
• Extracellular Matrix Stiffening Contributes to Cartilage Aging and Osteoarthritis
• The Gut Microbiome is Distinct in Parkinson's Disease
• A Method of Inducing Epigenetic Aging via Damage to DNA
• Tau Aggregation Drives Neuroinflammation via Transposable Element Activation
• Complaining About Hype in the Longevity Industry
• ADAR1 in Immunity and Aging
• A Role for Transposable Elements in Cellular Senescence
• The Impact of Aging on Skin Healing
• More on the Work of the Longevity Escape Velocity Foundation
• Age-Related Loss of Sense of Smell Correlates with Degree of Frailty
• Quantifying the Ability of Fasting and Exercise to Increase BDNF Expression
• Exploring Correlations Between Trace Elements in Drinking Water and Longevity
• Some Short-Chain Fatty Acids Made by Gut Microbes Increase Neuroinflammation in the Aging Brain
• Towards Ways to Encourage Cells to Degrade Greater Amounts of Tau Protein

Periodic Reprogramming via Gene Therapy Doubles Remaining Life Span in Old Mice
https://www.fightaging.org/archives/2023/01/periodic-reprogramming-via-gene-therapy-doubles-remaining-life-span-in-old-mice/

Perhaps the most important early measure of the quality of a given approach to the treatment of aging is its effect on remaining life span in old mice. Prevention is a good approach, but it has the disadvantage of only working to its greatest effect in those who are not yet old. The best approaches to the treatment of aging will produce rejuvenation, and thus be applicable to both (a) prevention of degenerative aging in people who are entering later life and (b) reversal of degenerative aging in those already suffering its effects. Reversal of the cell and tissue damage that causes aging, when periodically applied prior to the worst pathology of aging, is prevention. Allowing mice to age into dysfunction followed by application of a therapy to restore health and extend life is a good indication that the therapy is producing rejuvenation.

In today's preprint paper, researchers outline an interesting approach to partial reprogramming, a way to restore a more youthful pattern of gene expression in the cells present in aged tissue. Evidence to date suggests that widespread partial reprogramming in most tissues is beneficial. The research employed an adeno-associated virus (AAV)-mediated gene therapy to introduce a conditional construct into the cells of aged mice, allowing the expression of Yamanaka factors in response to oral administration of the antibiotic doxycycline. Partial reprogramming could therefore be induced intermittently in all of the cells transduced by the AAV vector for the remainder of the mouse life span. The researchers used AAV9, an AAV variant that tends to give decent coverage of the major organs at the dose used in this study. The result was a doubling of remaining life span in the treated mice. This was a small study, 20 mice to a group, but the size of the outcome is large, a compelling result.

The intravenous AAV dose used here was at the high end of the practical and safe range for mice, and there have been deaths in human clinical trials at an equivalent dose. It puts stress on the liver, for example. AAV as it stands is a poor choice for uses that will require high dose systemic administration in large numbers of older patients, for a variety of logistical and regulatory reasons. There must be improvements to the AAV technology, or better gene therapy options must arise to replace it. Some lipid nanoparticles (LNPs) show promise, but they must be coupled with a payload able to reliably deliver genetic machinery into the cell nucleus. Many lines of work seem potentially able to solve one or other of these challenges, but none have as yet reached the goal to become both robustly functional and readily available for other projects.

One of the ways in which we will come to see improvement in gene therapy technologies is the continued demonstration in animal studies of ever more compelling outcomes that can be achieved via their use. Sizeable extension of remaining life span in old mice, achieved via use of a hot-topic technology currently backed by billions in funding for research and development, is likely to draw increased investment in ways to deliver the important advance of a gene therapy capable of cost-effective, safe-enough whole body introduction of long-lasting genetic additions.

Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice

Using a cocktail of transcription factors, OCT4 (O), SOX2 (S), KLF4 (K), and c-MYC (M), collectively known as OSKM or Yamanaka factors, seminal studies showed that somatic cells can be reversed to a pluripotent state, thereby reversing a long-held paradigm of unidirectional differentiation. By short or cyclic induction of the Yamanaka factors in transgenic mice, investigators have demonstrated age extension in progeroid mice. These transgenic mouse models encoded a polycistronic OSKM cassette driven by a reverse tetracycline transactivator (rtTA) (4F mice); cyclic administration of doxycycline led to partial reprogramming without teratoma formation. This paradigm partially ameliorated aging phenotypes and extended the lifespan in the 4F-progeroid model. The study further showed that the epigenetic profile assessed by epigenetic methylation clocks of tissues, correlated with improved function.

The translation of these proof-of-concept genetic studies toward therapeutic interventions is to benefit the increasingly large aging population. In support of this endeavor, we have generated a systemically delivered two-part AAV9 system with doxycycline-inducible OSK, where one vector carried a constitutively expressed rtTa and the other vector contained a polycistronic OSK expression cassette driven by doxycycline responsive TRE promoter. We selected AAV9 capsid to ensure maximal distribution to most tissues. We injected 124-week-old wild type C57BL6/J mice retro-orbitally with 100 μl containing either PBS or 1E12 viral particles of each vector. We initiated the doxycycline induction for both the control and AAV administered groups the day after injections and alternated weekly on/off cycles for the remainder of the animals' lives.

Intriguingly, we observed a 109% extension in median remaining life in response to OSK expression (control mice had 8.86 weeks of life remaining vs. 18.5 weeks for TRE-OSK mice). Doxycycline-treated control mice had a median lifespan of ∼133 weeks, while the TRE-OSK mice had a median lifespan of 142.5 weeks. We observed a significant reduction in the frailty index from 7.5 points for doxycycline treated control mice to 6 points for TRE-OSK mice, suggesting that increased lifespan correlated to overall better health of the animals. We isolated DNA from heart and liver tissue from control and TRE-OSK treated mice at time of death and found that the Lifespan Uber Clock (LUC) for both liver and heart trended towards reduced epigenetic age.

Extracellular Matrix Stiffening Contributes to Cartilage Aging and Osteoarthritis
https://www.fightaging.org/archives/2023/01/extracellular-matrix-stiffening-contributes-to-cartilage-aging-and-osteoarthritis/

Age-related changes in the structure of the extracellular matrix that surrounds and supports cells are not as well studied as changes in cell behavior. Nonetheless, there is plenty of evidence for changes in the extracellular matrix to negatively affect tissue function. Cells create and maintain the matrix, but the state of the matrix in turn influences cells, and over time is affected by more than just cell behavior. Metabolic processes can alter and fragment elastin, cross-link collagen molecules, and so forth.

Cross-linking of matrix molecules occurs with age as a byproduct of the normal operation of metabolism, reducing flexibility and increasing stiffness. Targeting this cross-linking is a field still in its infancy, and only a few lines of research and development have made significant progress. Clinical trials of cross-link breaking in the lens of the eye have been undertaken, but this chemistry isn't relevant to the rest of the body. Some inroads have been made on finding ways to break down the persistent glucosepane cross-links that appear to be the most relevant to human extracellular matrix aging elsewhere in the body, but despite the launch of a company, Revel Pharmaceuticals, to develop these candidate treatments, there is still a long road ahead.

New mechanism uncovered behind osteoarthritis could inform new treatments

Osteoarthritis occurs when cartilage in a joint stiffens and begins to break down which then damages the underlying bone, resulting in pain, swelling and feelings of stiffness. There are currently no treatments to reverse this cartilage stiffening and resulting damage. Much has remained unknown about the molecular causes of this damage and how to treat it. These unknowns are especially germane to knee osteoarthritis, where no single event causes the cartilage damage, and the greatest predictive risk factor is aging.

Using advanced mass spectrometry technology, the researchers mapped out the trajectory of structural and protein changes in mice with knee osteoarthritis over the course of their lifetimes and according to sex. They then compared their findings to the current understanding of knee osteoarthritis in humans. The researchers found that Klotho was heavily involved in the molecular process that led to osteoarthritis. This work was an extension of previous studies showing that Klotho protects mitochondria within skeletal muscle and plays a key role in skeletal muscle regeneration following injury. As people age, their klotho levels go down, hence why it's referred to as a longevity protein.

The new analysis revealed that when knee cartilage tissue became stiffer, the gene that codes for Klotho was repressed. They verified this in models of young and old chondrocyte cells responsible for cartilage formation, which were seeded in environments designed to mimic young and old tissue stiffness. Young chondrocyte cells looked old when put on a stiff surface due to the loss of Klotho, but when the researchers protected the cells from the stiffness in their environment, they observed chondrocyte health.

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology. Using mass spectrometry proteomics followed by a series of genetic and pharmacological manipulations, we discovered that increased matrix stiffness drove Klotho promoter methylation, downregulated Klotho gene expression, and accelerated chondrocyte senescence in vitro.

In contrast, exposing aged chondrocytes to a soft matrix restored a more youthful phenotype in vitro and enhanced cartilage integrity in vivo. Our findings demonstrate that age-related alterations in extracellular matrix biophysical properties can initiate pathogenic mechanotransductive signaling that promotes Klotho promoter methylation and compromises cellular health. These findings are likely to have broad implications even beyond cartilage for the field of aging research.

The Gut Microbiome is Distinct in Parkinson's Disease
https://www.fightaging.org/archives/2023/01/the-gut-microbiome-is-distinct-in-parkinsons-disease/

Parkinson's disease is characterized by aggregation of α-synuclein, one of a number of harmful protein aggregates that form and spread in the aging brain. At present, it is thought that in many patients this process of aggregation starts in the intestines rather than in the brain. So it is perhaps not that surprising to find that alterations in the balance of microbial populations in the gut microbiome are characteristic of Parkinson's disease. Researchers have been looking into correlations between the microbiome and various age-related diseases with increasing energy for some years now.

Exactly how the gut microbiome contributes to Parkinson's is yet to be established. It may be as simple as the consequence of increased inflammatory signaling as populations of harmful microbes grow in number. That is an attractive argument, given the disruptive nature of chronic inflammation, but wagering on a biological process turning out to be simple is rarely a winning proposition. Regardless of underlying mechanisms, given that the state of the microbiome can be both measured via 16S rRNA sequencing and radically adjusted via fecal microbiota transplantation, there is the possibility of (a) effective screening for risk of Parkinson's, and perhaps (b) effective prevention via restoration of a healthy balance of microbial populations.

New study puts gut microbiome at the center of Parkinson's disease pathogenesis

Investigators employed metagenomics, the study of genetic material recovered directly from the stool microbiome of persons with Parkinson's disease (PD) and neurologically healthy control subjects. Investigators found an overabundance of opportunistic pathogens and immunogenic components, which suggest infection and inflammation at play, overproduction of toxic molecules, and overabundance of the bacterial product curli. This induces PD pathology and dysregulation of neurotransmitters, including L-dopa. At the same time, there was a shortage of neuroprotective molecules and anti-inflammatory components, which makes recovery difficult.

The researchers studied 257 species of organisms in the microbiome, and of these, analysis indicated 84, more than 30 percent, were associated with Parkinson's disease. Of the 84 PD-associated species, 55 had abnormally high abundance in persons with PD, and 29 were depleted. At one end of the spectrum, Bifidobacterium dentium was elevated by sevenfold, Actinomyces oris by 6.5-fold and Streptococcus mutans by sixfold. At the other end of the spectrum, Roseburia intestinalis was reduced by 7.5-fold and Blautia wexlerae by fivefold.

"Undoubtedly more information will be revealed as we increase the sample size and others also conduct metagenomics studies and share the data. We anticipate that in the near future we will have the tools and the analytic power to use metagenomics as a new approach to study PD heterogeneity, search for biomarkers, delve deeper into the origin and progression of PD sub-phenotypes, and investigate the potential in manipulating the microbiome to prevent, treat and halt the progression of PD."

Metagenomics of Parkinson's disease implicates the gut microbiome in multiple disease mechanisms

Parkinson's disease (PD) may start in the gut and spread to the brain. To investigate the role of gut microbiome, we conducted a large-scale study, at high taxonomic resolution, using uniform standardized methods from start to end. We enrolled 490 PD and 234 control individuals, conducted deep shotgun sequencing of fecal DNA, followed by metagenome-wide association studies to declare disease association, network analysis to identify polymicrobial clusters, and functional profiling.

Here we show that over 30% of species, genes, and pathways tested have altered abundances in PD, depicting a widespread dysbiosis. PD-associated species form polymicrobial clusters that grow or shrink together, and some compete. PD microbiome is disease permissive, evidenced by overabundance of pathogens and immunogenic components, dysregulated neuroactive signaling, preponderance of molecules that induce alpha-synuclein pathology, and over-production of toxicants; with the reduction in anti-inflammatory and neuroprotective factors limiting the capacity to recover.

A Method of Inducing Epigenetic Aging via Damage to DNA
https://www.fightaging.org/archives/2023/01/a-method-of-inducing-epigenetic-aging-via-damage-to-dna/

You may recall the work linking DNA double strand break repair to epigenetic changes characteristic of aging. Repeated cycles of this repair cause some form of depletion of necessary factors or other disarray in the mechanisms controlling gene expression. This is a compelling way to link random DNA damage, largely occurring in parts of the genome that are inactive in any given cell, largely occurring in cells that will not go on to divide many times, and occurring in completely different locations from cell to cell, to a consistent, characteristic aspect of aging. Beyond the question of cancer risk, the only other compelling way to connect stochastic DNA damage to the general declines of aging is to consider somatic mosaicism emerging as a result of mutational damage to stem cells, as that mutation spreads throughout a tissue.

In today's materials, researchers describe a way to accelerate this epigenetic change caused by repair of breaks in DNA, and characterize a mouse lineage engineered to undergo a great deal of DNA damage, but damage that occurs only in inactive portions of the genome, and should thus produce no harm to the genomic information needed for cell function. The result appears to be accelerated aging, occurring though the mechanism of epigenetic change noted above. This allows researchers to more readily test the use of partial reprogramming as a means to reverse this epigenetic change, and better understand how this reversal works.

As ever, one should be cautious about declaring models that focus on just one mechanism of aging to actually exhibit accelerated aging. Any form of biological damage run amok, such as occurs for DNA damage in progeroid syndromes, can produce outcomes that bear a strong resemblance to normal aging - but they are not normal aging. The details as to how exactly they are different are important when it comes to drawing conclusions from these models about the best approaches to treating aging. It is a little early in the research into DNA repair and epigenetic change for a good understanding as to how this sort of model will differ from normal aging, as researchers have for progeroid mice.

Loss of Epigenetic Information Can Drive Aging, Restoration Can Reverse It

A component of epigenetics is the physical structures such as histones that bundle DNA into tightly compacted chromatin and unspool portions of that DNA when needed. Genes are inaccessible when they're bundled up but available to be copied and used to produce proteins when they're unspooled. Thus, epigenetic factors regulate which genes are active or inactive in any given cell at any given time. By acting as a toggle for gene activity, these epigenetic molecules help define cell type and function. Since each cell in an organism has basically the same DNA, it's the on-off switching of particular genes that differentiates a nerve cell from a muscle cell from a lung cell.

The team's main experiment involved creating temporary, fast-healing cuts in the DNA of lab mice. These breaks mimicked the low-grade, ongoing breaks in chromosomes that mammalian cells experience every day in response to things like breathing, exposure to sunlight and cosmic rays, and contact with certain chemicals. In the study, to test whether aging results from this process, the researchers sped the number of breaks to simulate life on fast-forward. The team also ensured that most of the breaks were not made within the coding regions of the mice's DNA - the segments that make up genes. This prevented the animals' genes from developing mutations. Instead, the breaks altered the way DNA is folded.

The researchers called their system ICE, short for inducible changes to the epigenome. At first, epigenetic factors paused their normal job of regulating genes and moved to the DNA breaks to coordinate repairs. Afterward, the factors returned to their original locations. But as time passed, things changed. The researchers noticed that these factors got "distracted" and did not return home after repairing breaks. The epigenome grew disorganized and began to lose its original information. Chromatin got condensed and unspooled in the wrong patterns, a hallmark of epigenetic malfunction. As the mice lost their youthful epigenetic function, they began to look and act old. The researchers saw a rise in biomarkers that indicate aging. Cells lost their identities as, for example, muscle or skin cells. Tissue function faltered. Organs failed.

Next, the researchers gave the mice a gene therapy that reversed the epigenetic changes they'd caused. The therapy delivered a trio of genes - Oct4, Sox2, and Klf4, together named OSK - that are active in stem cells and can help rewind mature cells to an earlier state. The ICE mice's organs and tissues resumed a youthful state. The therapy set in motion an epigenetic program that led cells to restore the epigenetic information they had when they were young. How exactly OSK treatment achieved that remains unclear. At this stage, the discovery supports the hypothesis that mammalian cells maintain a kind of backup copy of epigenetic software that, when accessed, can allow an aged, epigenetically scrambled cell to reboot into a youthful, healthy state.

Loss of epigenetic information as a cause of mammalian aging

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

Tau Aggregation Drives Neuroinflammation via Transposable Element Activation
https://www.fightaging.org/archives/2023/01/tau-aggregation-drives-neuroinflammation-via-transposable-element-activation/

Evidence suggests that there is a bidirectional relationship between tau aggregation and inflammation in the aging brain. Both occur in all brains, and when present to a greater degree contribute to the neurodegenerative conditions termed tauopathies. The most well known of these is Alzheimer's disease, in which tau aggregates and their surrounding toxic biochemistry cause the widespread cell death and severe symptoms that characterize the final stages of the condition.

Various studies individually support each of the two directions of the relationship between tau and inflammation. Removing senescent cells from the brain dampens inflammatory signaling, and thereby reduces tau pathology, for example. Here, researchers demonstrate a mechanism by which tau aggregation encourages transposable element activity that in turn provokes an inflammatory response. We might view the later stages of many neurodegenerative conditions as runaway feedback loops in which inflammation produces consequences that encourage further inflammation.

Pathogenic tau-induced transposable element-derived dsRNA drives neuroinflammation

Deposition of tau protein aggregates in the brain of affected individuals is a defining feature of "tauopathies," including Alzheimer's disease. Studies of human brain tissue and various model systems of tauopathy report that toxic forms of tau negatively affect nuclear and genomic architecture, identifying pathogenic tau-induced heterochromatin decondensation and consequent retrotransposon activation as a causal mediator of neurodegeneration. On the basis of their similarity to retroviruses, retrotransposons drive neuroinflammation via toxic intermediates, including double-stranded RNA (dsRNA).

We find that dsRNA and dsRNA sensing machinery are elevated in astrocytes of postmortem brain tissue from patients with Alzheimer's disease and progressive supranuclear palsy and in brains of tau transgenic mice. Using a Drosophila model of tauopathy, we identify specific tau-induced retrotransposons that form dsRNA and find that pathogenic tau and heterochromatin decondensation causally drive dsRNA-mediated neurodegeneration and neuroinflammation. Our study suggests that pathogenic tau-induced heterochromatin decondensation and retrotransposon activation cause elevation of inflammatory, transposable element-derived dsRNA in the adult brain.

Complaining About Hype in the Longevity Industry
https://www.fightaging.org/archives/2023/01/complaining-about-hype-in-the-longevity-industry/

The author of this commentary is overly critical of the science of rejuvenation as a whole, if one takes a tour of his work, but here he makes legitimate points about the harms done by an excess of hype. He picks on one of the easier targets, the publicity that David Sinclair has generated for his work, initially on sirtuins and later on reprogramming, with which it is fairly easy to find issues. Raising awareness, marketing potential programs, is a necessary evil in the matter of directing funding into new fields, but unrealistic promises sustained over time become damaging.

Is aging treatable? In the sense that the rate of aging can be modified by genes and the environment, yes. However, aging is easy to accelerate, i.e. by smoking, overweight, infectious diseases, and other factors, and much harder to slow. Do sirtuins extend lifespan in yeast, invertebrates and vertebrates? Has David Sinclair discovered sirtuin activators? Based on 25 years of work by academic and industrial investigators, the clear answer to both questions is no. Whereas Sinclair claims that sirtuins are dominantly acting longevity genes from yeast to humans, early reports of sirtuins extending lifespan in invertebrates could not be independently replicated. In 2011, researchers from 7 institutions published together that sirtuin genes do not extend lifespan in worms or flies.

Sinclair's theories were au courant for two decades. Indeed, sirtuins and resveratrol have been subjects of hundreds of stories in the mass media. A 2008article reported that sirtuin activators would be developed as diabetes medications that, as a side effect, would extend lifespan. The global interest in sirtuins and sirtuin activators was such that companies - most notably GSK - spent many billions trying to get a positive result and could not because the so-called sirtuin activators do not activate sirtuins and because sirtuins are not longevity genes. Sinclair's book Lifespan therefore represents a pivot in which a person central to the failure of the largest longevity medicine program in pharmaceutical history turns to the general public to retell his story. In the retelling, sirtuins are longevity genes and sirtuin activators are real.

ADAR1 in Immunity and Aging
https://www.fightaging.org/archives/2023/01/adar1-in-immunity-and-aging/

This short overview skims recent work on the role of ADAR1 expression in aging. Levels of ADAR1 are reduced with age in many tissues, and this may affect a number of processes relevant to aging, such as cellular senescence. ADAR1 edits RNA, affecting the behavior of gene expression at a very low level. It is a good example of a protein that is thus involved in many, many processes in the cell, and which has indirect effects on any number of cell behaviors. It is exceptionally challenging to pin down specific important roles for such proteins. There is such a large space of possibilities to cover that decades of work may or may not arrive at the crucial realizations and studies that turn out to demonstrate a possible way forward to intervene in aging.

Researchers recently published five papers on the function and molecular mechanism of ADAR1 (adenosine deaminases acting on RNA) in aging, cancer, and autoimmune diseases. Four of the papers revealed that ADAR1 regulates autoimmune disease and cancer immunotherapy through canonical adenosine-to-inosine (A-to-I) RNA editing. Using a different approach, the fifth paper discovered that ADAR1 could suppress cellular senescence by regulating p16INK4a expression through an RNA editing independent pathway.

Researchers found that ADAR1 could promote the interaction between human antigen R (HuR) and SIRT1 mRNA, thereby increasing the stability of SIRT1 mRNA. The elevated SIRT1 expression, in turn, suppresses the translation of p16INK4a mRNA, thus inhibiting the occurrence of senescence. However, in aging cells, ADAR1 is degraded by lysosomal-mediated autophagy. Researchers found that the protein level of ADAR1 in the brain, ovary, and other tissues of aging mice was significantly lower than that of young mice. Because the ADAR1 mRNA expression level did not change significantly, this result indicates that the down-regulation of ADAR1 expression during aging mainly happened at the post-transcriptional level.

The researchers also found that applying small molecule inhibitors targeting the lysosomal autophagy pathway in aging cells could inhibit the loss of ADAR1 expression due to aging. Overall, the study revealed a novel mechanism of autophagy in promoting aging and indicated that the altered ADAR1 expression might be a biomarker of aging. Importantly, modulating ADAR1 expression levels may be potent in treating aging-related diseases.

A Role for Transposable Elements in Cellular Senescence
https://www.fightaging.org/archives/2023/01/a-role-for-transposable-elements-in-cellular-senescence/

Transposable elements are largely the remnants of ancient viral infections, DNA sequences capable of copying themselves within the genome via a number of different mechanisms. Transposable elements are suppressed in youth, but this suppression breaks down with age, and the resulting disruptive activity may provide a meaningful contribution to degenerative aging. Separately, researchers are finding that transposable elements are active in senescent cells, and contribute to some of the behaviors that make lingering senescent cells harmful in aged tissues, as noted in this paper.

Silent long-interspersed element-1 (LINE1) retrotransposons, belonging to non-long terminal repeat (non-LTR) retrotransposons, can be activated during senescence, triggering the innate immune response that is responsible for part of the senescence-associated phenotypes. A different class of retroelements, endogenous retroviruses (ERVs), belonging to LTR retrotransposons are a relic of ancient retroviral infection, fixed in the genome during evolution, comprising about 8% of the human genome. As a result of evolutionary pressure, most human ERVs (HERVs) accumulate mutations and deletions that prevent their replication and transposition function. However, some evolutionarily young subfamilies of HERV proviruses, such as the recently integrated HERVK human mouse mammary tumor virus like-2 (HML-2) subgroup, maintain open reading frames encoding proteins required for viral particle formation.

Except at specific stages of embryogenesis when DNA is hypomethylated and under certain pathological conditions such as cancer, HERVs are transcriptionally silenced by host surveillance mechanisms such as epigenetic regulation in post-embryonic developmental stages. Notably, whether ERVs can escape host surveillance during aging and, if so, what effects they may exert on cellular and organismal aging are still poorly investigated.

In this study, using cross-species models and multiple techniques, we revealed an uncharacterized role of endogenous retrovirus resurrection as a biomarker and driver for aging. Specifically, we identified endogenous retrovirus expression that was associated with cellular and tissue aging and that the accumulation of HERVK retrovirus-like particles (RVLPs) mediates the aging-promoting effects in recipient cells. These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. We can thus inhibit endogenous retrovirus-mediated pro-senescence effects to alleviate cellular senescence and tissue degeneration in vivo, suggesting possibilities for developing therapeutic strategies to treat aging-related disorders.

The Impact of Aging on Skin Healing
https://www.fightaging.org/archives/2023/01/the-impact-of-aging-on-skin-healing/

Skin heals poorly in old people, the consequence of mechanisms of aging such as the growing number of senescent cells present in aged tissues. Senescent cells are normally generated for a short period of time during wound healing and their pro-growth, pro-inflammatory signals help to coordinate the intricate dance of cell populations involved in regrowth following injury. The constant presence of senescent cells and their signals is disruptive to the healing process, however. As noted in this review paper, a number of other mechanisms are also relevant to the declining capacity for regeneration of skin in older people.

Skin is the human's largest organ and consists of three distinctive layers, the epidermis, dermis, and hypodermis. Skin is equipped with an innate immune response towards tissue injury, with the aim to restore normal tissue structure and function. The normal wound healing process comprises three distinctive stages, inflammation, reepithelialization, and tissue remodelling. The balance between inflammation and its control is essential to maintain a normal wound healing process. This is because acute inflammation at the early stage of wound healing is beneficial in removing cell debris and invading microbes. However, if the inflammation state is prolonged, this will lead to further destruction of adjacent cells and eventually inhibit wound healing.

Aging causes more platelets to adhere to the injured epithelium. This will cause the production of more pro-inflammatory cytokines such as PDGF, TGF-β, and TGF-α. In response to their release, neutrophils will rapidly be recruited to the site of injury. Simultaneously, monocytes will also be recruited to the site of injury. However, since monocytes are larger in size, they require specific adhesion molecules such as ICAM-1 and VCAM-1 to be expressed on the endothelial surface in order to infiltrate the site of injury. In aged skin, these adhesion molecules are greatly reduced, and this impairs the monocyte infiltration.

Reactive oxygen species (ROS) also have an important role in the wound healing process. They are produced by neutrophils and macrophages via NADPH oxidase and help in killing microbes and preventing wound infection. They also have a role as a vasoconstrictor to help reduce blood flow and promote thrombus formation soon after injury. Oxidative stress is also necessary for transition into the proliferative phase. A low amount of ROS provides positive effects on wound healing, whereas prolonged exposure to ROS has a detrimental effect on the wound healing process. Increased production of ROS, such as nitric oxide and superoxide anions, will increase tissue damage and impair healing. In aged skin, more ROS will accumulate due to prolonged inflammation. Hence, this will prolong the state of oxidative stress.

Aged skin will usually have damaged and impaired growth of blood vessels. Once the microcirculation is impaired, there are changes in the inflammatory response due to a reduction in the inflammatory cells and chemical mediators being able to reach the site of injury. On top of that, it also means that there is a relative hypoperfusion at the injury site, leading to less nutrients and oxygen being able to be supplied to support the wound healing process. Temporary hypoxia is important in wound healing process as it can stimulate the release of cytokines and growth factors to induce cell proliferation, migration, as well as angiogenesis. However, a prolonged hypoxia state will negatively affect the wound healing process.

More on the Work of the Longevity Escape Velocity Foundation
https://www.fightaging.org/archives/2023/01/more-on-the-work-of-the-longevity-escape-velocity-foundation/

The Longevity Escape Velocity Foundation (LEVF) is initially working to assess combinations of approaches to the treatment of aging, to assess the degree to which mouse life span is affected. Aging consists of many distinct mechanisms, and comprehensive rejuvenation will require a diverse package of therapies. Yet the research and development community undertakes little work on combined treatments. Here, the Lifespan.io team talks to Aubrey de Grey about some of the details of the work presently under way.

We are obviously very excited about LEVF's robust mouse rejuvenation (RMR) project. Could you walk our readers through its design and goals?

This is envisioned as a rolling research program aiming to increase both the mean and maximum lifespan of mice by at least 12 months with various combination therapies started late in life. For the first study, four therapies have been chosen: rapamycin, a senolytic, hematopoietic stem cell transplantation (HSCT), and telomerase expression. I believe we'll have two outcomes. One of them scientific, and the other more, if you like, rhetorical. We want to get mice to live a lot longer than they do now: at least a year longer, starting the treatment or treatments only after middle age. The idea is that this will appeal more directly to people who care, vote, pay taxes, and make donations than if you do early-onset interventions. So, I decided to put numbers on this, to have a milestone that clearly says this is where we want to get to. We believe this will be a sufficiently dramatic result.

With such a lofty goal at hand, would you like to make some predictions about the results? For instance, which interventions or combinations are more likely to succeed?

Definitely not. Let's be clear: I do not actually have lofty expectations for this first experiment. We've been saying from the beginning that this is a rolling research program, and our top priority is, as soon as we get this one kicked off, we're going to design the next one, and to bring in the funding, which is about three million for each round. So, no, I have no idea what we're going to get with this one, but I'm hoping that we'll be able to do subsequent rounds more than once a year - maybe every nine months or so - because we don't need to wait for the results of the first one to decide how to do the second one. We're also incorporating masses of information from the community, from literature, and we already have a plenty good list of things that we'd like to try in the next round.

Have you decided on what senolytic will be used?

Yes, we just decided on it. We're going to use conjugated navitoclax. As you probably know, navitoclax has a reputation as a reasonably good senolytic. However, it's not very specific. But researchers had this extraordinarily simple and brilliant idea based on the fact that most senescent cells have a high expression of beta-galactosidase. You covalently attach galactose to the molecule in a location that makes the molecule not work. But because it's galactose, if the cell is producing beta-galactosidase, galactose will be cleaved off in senescent cells and only in senescent cells.

What will you be measuring?

We're going to measure all sorts of stuff in addition to lifespan. We will focus heavily on function with tests such as the rotarod, so that we have good information on healthspan. We'll be doing that in different ways. First, we'll have a bunch of non-invasive things that measure agility, visual acuity, physical appearance, including alopecia and kyphosis (the bending of the spine). These are well-established measures of biological age. In addition, we will be sacrificing some mice at various periods during the study and asking what condition they're in. On top of that, we will be looking at mice that die naturally during the experiment and figuring out what they died of. So, we're really covering all the bases.

Age-Related Loss of Sense of Smell Correlates with Degree of Frailty
https://www.fightaging.org/archives/2023/01/age-related-loss-of-sense-of-smell-correlates-with-degree-of-frailty/

The many aspects of degenerative aging arise from a smaller set of common underlying processes of damage, giving rise to a web of interacting consequences. It can be hard to pin down the chains of cause and effect, and the degree to which any one contributing cause is responsible for the end result, but nonetheless many aspects of aging correlate with one another for the simple reason that the root causes are much the same. This can be the case even when degeneration occurs in very different bodily systems. For example, as shown here, loss of sense of smell and general physical frailty show a correlation.

To examine the relationship between frailty and olfaction, the research team analyzed data from 1,160 older adults enrolled in the National Social Life, Health and Aging Project between 2015 and 2016. The mean age of subjects was 76 and 55.7% were female. Participants were exposed to five scents to measure olfactory identification and six scents to measure sensitivity levels. Results were then matched to a subject's frailty score.

Researchers concluded that for every one-point increase in both olfactory identification and sensitivity scores, there was a significant and meaningful reduction in frailty status, implying that improvements in smell were associated with improved health status and resilience of older results. Conversely, the worse the sense of smell, the frailer a subject was, suggesting that smell loss can be a measurable biomarker and potential risk factor for frailty in older adults.

Although these findings in older adults add to a body of literature that suggests the sense of smell can be a bellwether of frailty and impending mortality, the relationship of these unique sensory losses with unhealthy aging over time is unclear. Common consequences of smell loss include a loss of appetite, difficulty monitoring personal hygiene, depression, and an inability to detect toxic fumes. In older adults, this may be associated with weight loss, malnutrition, weakness, inadequate personal care, and even potential injuries caused by gas leaks or fires.

Quantifying the Ability of Fasting and Exercise to Increase BDNF Expression
https://www.fightaging.org/archives/2023/01/quantifying-the-ability-of-fasting-and-exercise-to-increase-bdnf-expression/

Upregulation of BDNF is a useful goal, as it produces greater neurogenesis in the brain. Neurogenesis, the production of new neurons from neural stem cells, and their integration into neural circuits, is important in memory, learning, and the resilience of the brain to damage and aging. Increased levels of BDNF may also improve metabolism and reduce inflammation in brain tissue. BDNF levels decline with age, but evidence suggests that BDNF expression can be boosted via calorie restriction and exercise. Researchers here compare these approaches for effectiveness, finding that short bursts of high intensity exercise produce the best outcome.

The specialised protein named brain-derived neurotrophic factor (BDNF) promotes neuroplasticity (the ability of the brain to form new connections and pathways) and the survival of neurons. Animal studies have shown that increasing the availability of BDNF encourages the formation and storage of memories, enhances learning, and overall boosts cognitive performance. These key roles and its apparent neuroprotective qualities have led to the interest in BDNF for ageing research.

To tease apart the influence of fasting and exercise on BDNF production researchers compared the following factors to study the isolated and interactive effects: (a) fasting for 20 hours; (b) light exercise (90-minute low intensity cycling); (c) high-intensity exercise (six-minute bout of vigorous cycling); and (d) combined fasting and exercise. Twelve physically active participants (six males, six females aged between 18 and 56 years) took part in the study. The researchers found that brief but vigorous exercise was the most efficient way to increase BDNF compared to one day of fasting with or without a lengthy session of light exercise. BDNF increased by four to five-fold (396 pg/L to 1170 pg/L) more compared to fasting (no change in BDNF concentration) or prolonged activity (slight increase in BDNF concentration, 336 pg/L to 390 pg/L).

The cause for these differences is not yet known and more research is needed to understand the mechanisms involved. One hypothesis is related to the cerebral substrate switch and glucose metabolism, the brain's primary fuel source. The cerebral substrate switch is when the brain switches its favoured fuel source for another to ensure the body's energy demands are met, for example metabolising lactate rather than glucose during exercise. The brain's transition from consuming glucose to lactate initiates pathways that result in elevated levels of BDNF in the blood. The observed increase in BDNF during exercise could be due to the increased number of platelets (the smallest blood cell) which store large amounts of BDNF. The concentration of platelets circulating in the blood is more heavily influenced by exercise than fasting, and increases by 20%.

Exploring Correlations Between Trace Elements in Drinking Water and Longevity
https://www.fightaging.org/archives/2023/01/exploring-correlations-between-trace-elements-in-drinking-water-and-longevity/

Studies of the variance in human longevity due to genetics and environment are a matter of chasing small effect sizes, modest increases in the (still low) odds of living to extreme old age, and trying to distinguish those effects from the much larger impact of lifestyle choices and wealth. It isn't an easy endeavor, and at the end of the day small effect sizes are not the starting point from which to build ways to meaningfully extend the healthy human life span. Nonetheless, there is a great deal of this sort of research out there, interesting in its own right, but not the road to the future. The example here focuses on trace elements in drinking water, and might be compared with similar work focused on lithium intake via drinking water.

Longevity, as a complex life-history trait, shares an ontogenetic relationship with other quantitative traits, such as epigenetic and environmental factors. Therefore, it is important to identify environmental factors that may modify the epigenome to establish healthy aging. This study explored the association between tap drinking water and longevity in Cilento, Italy, to understand whether trace elements in local drinking water may have an influence on old, nonagenarian, and centenarian people and promote their health and longevity.

Data on population and water sources were collected through the National Demographic Statistics, the Cilento Municipal Archives, and the Cilento Integrated Water Service. Ordinary least squares (OLS) regression and a geographically weight regression (GWR) model were used to study the spatial relationship between the explanatory and outcome variables of longevity.

The results of the study showed that the prevalence of longevity is concentrated in the central, northern and southeastern areas of the territory and that some trace elements present in tap water may contribute to local longevity in Cilento. Specifically, all Cilento municipalities had alkaline tap water, and the municipalities with the highest longevity concentrations had higher alkalinity levels than the other municipalities, soft to medium-hard water hardness, an amount of total dissolved solids equivalent to the level of excellent water, lower amounts of sodium, adequate iron concentration, and adequate dietary intake of manganese per day.

Some Short-Chain Fatty Acids Made by Gut Microbes Increase Neuroinflammation in the Aging Brain
https://www.fightaging.org/archives/2023/01/some-short-chain-fatty-acids-made-by-gut-microbes-increase-neuroinflammation-in-the-aging-brain/

Researchers are attempting to determine exactly how the gut microbiome contributes to age-related chronic inflammation, particularly inflammation in the brain. This may be largely due to a few compounds produced by specific microbial species, some of which become more populous with age at the expense of beneficial microbes. The results noted here are an example of the output of this sort of research. Ultimately, this will lead to more deterministic ways of adjusting the gut microbiome in older individuals. At present the most effective approach is to transplant a fecal sample from a young individual, sidestepping our comparative ignorance of the fine details. It should be possible to improve upon this, however, given greater understanding of the interaction between the gut microbiome and the brain.

Evidence is accumulating that the gut microbiomes in people with Alzheimer's disease can differ from those of healthy people. But it isn't clear whether these differences are the cause or the result of the disease - or both - and what effect altering the microbiome might have on the course of the disease. To determine whether the gut microbiome may be playing a causal role, the researchers altered the gut microbiomes of mice predisposed to develop Alzheimer's-like brain damage and cognitive impairment.

When such genetically modified mice were raised under sterile conditions from birth, they did not acquire gut microbiomes, and their brains showed much less damage at 40 weeks of age than the brains of mice harboring normal mouse microbiomes. When such mice were raised under normal, nonsterile conditions, they developed normal microbiomes. A course of antibiotics at 2 weeks of age, however, permanently changed the composition of bacteria in their microbiomes. For male mice, it also reduced the amount of brain damage evident at 40 weeks of age.

Further experiments linked three specific short-chain fatty acids - compounds produced by certain types of gut bacteria as products of their metabolism - to neurodegeneration. All three of these fatty acids were scarce in mice with gut microbiomes altered by antibiotic treatment, and undetectable in mice without gut microbiomes. These short-chain fatty acids appeared to trigger neurodegeneration by activating immune cells in the bloodstream, which in turn somehow activated immune cells in the brain to damage brain tissue. When middle-aged mice without microbiomes were fed the three short-chain fatty acids, their brain immune cells became more reactive, and their brains showed more signs of tau-linked damage.

Towards Ways to Encourage Cells to Degrade Greater Amounts of Tau Protein
https://www.fightaging.org/archives/2023/01/towards-ways-to-encourage-cells-to-degrade-greater-amounts-of-tau-protein/

Researchers here report on an investigation of mechanisms regulating the turnover of tau protein in brain cells. The hope is to find approaches that will more aggressively clear the tau aggregates found in neurodegenerative conditions via the usual cell maintenance processes responsible for breaking down excess proteins, such as autophagy and proteasomal degradation. It is far too early to say how promising this approach might turn out to be at the end of the day, but the initial exploration is interesting.

A novel screening approach led researchers to 11 new in vivo validated tau regulators. Of these, three targets - ubiquitin-specific protease 7 (USP 7), RING-Type E3 Ubiquitin Transferase (RNF130), and RING-Type E3 Ubiquitin Transferase (RNF149) - converged on the ubiquitin protein degradation pathway. The majority of intracellular proteins within all tissues are degraded by the ubiquitin-proteasomal pathway. This is a complex, tightly regulated process involving several discrete and successive steps. Ubiquitin molecules are first activated and transferred to carrier proteins. Multiple ubiquitin molecules are attached to the protein substrate via a group of enzymes called the E3 ubiquitin ligases. Finally, the ubiquitinated substrate is degraded.

Previous studies have implicated the ubiquitin ligase, CHIP (C-terminus of Hsc70-interacting protein), as an important regulator of tau turnover and a critical player in the selective elimination of abnormal tau species. Interestingly, in this study, the researchers discovered that USP7 stabilizes tau by protecting it from CHIP-mediated degradation. They also found that RNF130 and RNF149 decrease the levels of the tau degrader (CHIP) and that their inhibition increases CHIP which in turn decreases tau levels. To test if these target genes can regulate CHIP and tau levels in the brain, the team turned off their expression in adult mice that overexpress mutant tau.

"Turning off the expression of USP7, RNF130, or RNF149 in adult mice with tauopathy using a doxycycline-inducible system increased CHIP level, and reduced total and phosphorylated-tau proteins. We also saw a decrease in other tell-tale signs of tau pathology and neuroinflammation. Most excitingly, these mice performed as well as age-matched normal mice in tasks that require learning and memory - a strong indicator that increasing CHIP levels in addition to a concomitant reduction in tau levels can improve neuronal and overall brain function in these mice."