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.

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.

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.

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."

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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%.

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.

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.

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."