Fight Aging!

Altered, misfolded forms of TDP-43 are thought to contribute to neurodegeneration in a number of age-related conditions, primarily amyotrophic lateral sclerosis and frontotemporal dementia. As is the case for other misfolded proteins associated with neurodegeneration, aberrant TDP-43 may accumulate in much of the older population to levels sufficient to meaningfully contribute to cognitive decline. That TDP-43 has this negative impact is a relatively recent discovery, and in comparison to amyloid-β, tau, and α-synuclein little is known of the mechanisms by which TDP-43 aggregation causes dysfunction and death in brain cells. This doesn't stop the development of therapies that aim to clear forms of TDP-43, but it would be beneficial to have confirming data to demonstrate that the specific target is the right one.

In today's research materials, scientists report on a step forward in understanding how aggregated TDP-43 causes cell death. There are no well-proven animal models of TDP-43 aggregation, in part because some of the details of TDP-43 pathology involve mechanisms specific to the human version of the protein, so the researchers built cell models in order to explore changes in cell function induced by the presence of TDP-43. They found a good candidate for further exploration in the form of NPTX2, a synaptic protein that appears to be upregulated to toxic levels in neurons affected by TDP-43 aggregation. It remains to be seen as to how this finding will progress to the clinic in the absence of animal models of the condition.

Cracking the code of neurodegeneration: New model identifies potential therapeutic target

Despite the identification of the aberrant accumulation of a protein called TDP-43 in neurons in the central nervous system as a common factor in the vast majority of amyotrophic lateral sclerosis (ALS) and about half of frontotemporal dementia (FTD) patients, the underlying cellular mechanisms driving neurodegeneration remain largely unknown. Researchers have now developed a novel neural cell culture model called "iNets," derived from human induced pluripotent stem cells. The cultures lasted exceptionally long - up to a year - and were easily reproduced.

Employing the iNets model, the researchers identified a toxic accumulation of NPTX2, a protein normally secreted by neurons through synapses, as the missing link between TDP-43 misbehavior and neuronal death. To validate their hypothesis, they examined brain tissue from deceased ALS and FTD patients and indeed found that, also in patients, NPTX2 accumulated in cells containing abnormal TDP-43. This means that the iNets culture model accurately predicted ALS and FTD patient pathology. In additional experiments in the iNets model, the researchers tested whether NPTX2 could be a target for drug design to treat ALS and FTD. The team engineered a setup in which they lowered the levels of NPTX2 while neurons were suffering from TDP-43 misbehavior. They found that keeping NPTX2 levels low counteracted neurodegeneration in the iNets neurons.

A model of human neural networks reveals NPTX2 pathology in ALS and FTLD

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies, which involve human-specific mechanisms that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors.

Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3′ untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity.

Researchers here use data on air pollution from a single US metropolitan area to show a correlation with Alzheimer's disease risk. Air pollution is shown to increase chronic inflammation via the interaction of particulates with lung tissue, and inflammation is an important component of the onset and progression of neurodegenerative conditions such as Alzheimer's disease. That said, the researchers were primarily interested in traffic as a source of particulate air pollution, and one might think that this introduces a correlation with wealth, given the usual distribution of cost of living versus proximity to major flows of traffic. Wealth and health are a part of a web of correlations including socioeconomic status, life expectancy, education, intelligence, and so forth. It requires some effort to untangle these contributions in human data.

For the study, researchers examined the brain tissue of 224 people who agreed to donate their brains at death to advance research on dementia. The people had died at an average age of 76. Researchers looked at the traffic-related air pollution exposure based on the people's home address in the Atlanta area at the time of death. Traffic-related PM2.5 concentrations are a major source of ambient pollution in urban areas like the metro-Atlanta area where most donors lived. The average level of exposure in the year before death was 1.32 micrograms per cubic meter (µg/m3) and 1.35 µg/m3 in the three years before death.

Researchers then compared pollution exposures to measures of the signs of Alzheimer's disease in the brain: amyloid plaques and tau tangles. They found that people with higher exposures to air pollution one and three years before death were more likely to have higher levels of amyloid plaques in their brains. People with 1 µg/m3 higher PM2.5 exposure in the year before death were nearly twice as likely to have higher levels of plaques, while those with higher exposure in the three years before death were 87% more likely to have higher levels of plaques.

Researchers also looked at whether having the main gene variant associated with Alzheimer's disease, APOE e4, had any effect on the relationship between air pollution and signs of Alzheimer's in the brain. They found that the strongest relationship between air pollution and signs of Alzheimer's was among those without the gene variant.

Link: https://www.eurekalert.org/news-releases/1034615

BAM15 is the result of attempts to produce a safe drug that induces mitochondrial uncoupling. Too much mitochondrial uncoupling will cause death by overheating, but modest degrees of this process can improve health and induce weight loss, as demonstrated in humans by the 20th century use of the somewhat dangerous mitochondrial uncoupler DNP. Here, researchers demonstrate a small extension of life in flies resulting from treatment with BAM15. Short-lived species exhibit a much greater plasticity of life span in response to interventions, so one shouldn't expect long-lived mammals such as humans to see any meaningful change in life span based on this work. Still, mitochondrial uncoupling does produce health benefits, provided it is constrained to a safe level.

Mitochondria are essential for survival and as such, impairments in organelle homeostasis significantly accelerate age-related morbidity and mortality. Here, we determined the contribution of bioenergetic efficiency to life span and health span in Drosophila melanogaster utilizing the mitochondrial uncoupler BAM15. Life span was determined in flies fed a normal diet (ND) or high fat diet (HFD) supplemented with vehicle or BAM15. Locomotor function was determined by negative geotaxis assay in middle-aged flies fed vehicle or BAM15 under ND or HFD conditions. Redox capacity, citrate synthase, mitochondrial DNA content, gene expression, and protein expression were assessed in flight muscle homogenates of middle-aged flies fed vehicle or BAM15 ND.

The molar ratio of H2O2 and O2 (H2O2:O2) in a defined respiratory state was calculated as a measure of redox balance. BAM15 extended life span by 9% on ND and 25% on HFD and improved locomotor activity by 125% on ND and 53% on HFD. Additionally, BAM15 enhanced oxidative phosphorylation capacity. Concurrently, BAM15 enhanced the mitochondrial H2O2 production rate, reverse electron flow from mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) to Complex I, mGPDH, and Complex I without altering the H2O2:O2 ratio. BAM15 upregulated transcriptional signatures associated with mitochondrial function and fitness as well as antioxidant defense.

In conclusion, BAM15-mediated restriction of bioenergetic efficiency prolongs life span and health span in Drosophila fed a ND or HFD. Improvements in life span and health span in ND were supported by synergistic enhancement of muscular redox capacity.

Link: https://doi.org/10.1111/acel.14107

Ichor Life Sciences is one of the earliest longevity industry companies, an interesting mix of contract research organization (CRO), biotech working on several different therapeutics, and investor in very early stage biotech startups. One of the Ichor co-founders here offers an interesting, though possibly biased perspective on how investors should behave in the biotech space. Inside companies, every new development program in the biotech industry starts with an attempt to replicate the research results that form the basis for the program, even given the existence of detailed, published papers and a coven of accessible researchers who suggest that it works. That replication often fails. Cellular biology is complicated, and many papers cannot be reproduced easily or at all. So why don't biotech investors do this before investing?

'VCs should run experiments to derisk longevity biotech investments'

"It always surprises me how willing a venture capital firm is to write a $5 million check but will not run a $10k experiment to replicate key findings from a potential investee. This is especially surprising given the reproducibility crisis that exists in the life sciences." Before making an investment in an early-stage biotech, Ichor CEO Kelsey Moody says Ichor first makes sure it can replicate the key preclinical findings of the company seeking funding. "Importantly, this process also allows us to obtain a clear understanding of where the technical hurdles are for these companies, and this also serves to de-risk investments for our angel network when they syndicate on deals with us."

"Unfortunately, in an effort to dazzle investors and get money, most companies cannot have a frank conversation about what their biggest development challenges are going to be. In many instances, we see these challenges are quite predictable (and therefore manageable) provided one is aware of them ahead of time. It also gives us a competitive edge. We see many 'diamond in the rough' deals that VCs will not touch, but we can move forward collaboratively with the investee very rapidly because of our knowledge on the bench and willingness to work through technical challenges."

Why don't we live in a world in which biotech investors put 1% of their investment into running a confirming study before proceeding? There are a number of plausible reasons, but the largest would be that investors don't run their own in-house laboratory and vivarium teams. $10k would barely pay for an acknowledgement of the time of day from a CRO if one is outsourcing the study. The economics of running a venture capital fund are interesting, but at the core of it, the money they manage is not their own, it belongs to the limited partners. Fund managers take a yearly fee of invested capital (typically 2%) and a cut of profits at the end of the day (typically 20%), and that 2% has to keep the lights on and the fund running. It is by no means enough funding to be running a laboratory and vivarium on the side. All but the largest funds are just about getting by on the day to day costs, given the necessary expenses of diligence, travel, offices, and so forth.

The second important reason is that studies take time. If outsourcing, it is reasonable to expect six months, end to end, for a short study to be planned, designed, scheduled, and conducted. Three months would be a heroic effort and require, at the very least, an established relationship with a friendly CRO that has resources held back to support the investor. While large institutional rounds of fundraising can certainly take six months to come together, early stage investment is a lot faster than that. Any investor that took months to decide whether they even liked the science would lose the best deals to other investors: the present venture capital industry clearly demonstrates that investors can move fast and be successful enough to convince limited partners to fund them. Speed is a competitive advantage.

Lastly, biotech investors, either individual or institutional, largely have a poor understanding of the science involved in any given project. This is not the image that biotech funds like to present, but it is definitely the reality under the hood. Very few funds employ people with a strong grasp of any specific part of the field, and even then it is a roll of the dice as to whether an interesting company is based on science that is easily understood by the fund consultants and employees. This is not an environment in which an investor could be expected to know how to arrange, design, and run a replication study. Investors are not the subject matter experts in the room - the experts are all in the company they are deciding whether or not to invest in.

Researchers here note one of a broad range of examples in which age-related changes in the state and behavior of non-cancerous cells results in a more hospitable environment for the growth of neighboring cancerous tissue. Cancer is an age-related condition not just because of increased damage to cells in older tissues, nor just because the immune system falters in its surveillance of potentially cancerous cells, but also due to other maladaptive changes that favor the metabolism and growth of some forms of cancerous cells.

A new study provides clues as to why pancreatic cancer is more common and aggressive in older people. It may also help scientists develop new therapeutic approaches for this difficult-to-treat cancer. The study showed that aging alters fibroblasts in ways that enable them to promote pancreatic cancer tumor growth. Researchers compared samples of pancreatic fibroblasts from patients older than 55 with pancreatic fibroblasts from patients younger than 35. They discovered that the cells from older patients behave very differently than younger ones. To find out why, they compared the proteins released by the younger and older cells and noted profound differences.

The researchers determined that a critical change in older pancreatic fibroblasts is that they release more of a protein called growth/differentiation factor 15 (GDF-15). When the team treated young mice with pancreatic tumors with GDF-15, it caused the tumors to grow more rapidly, just as they do in older mice. Older mice that were genetically engineered to lack the gene encoding GDF-15 had reduced pancreatic tumor growth.

Experiments in human cells and mouse models revealed that GDF-15 activates the AKT signaling pathway in an age-dependent manner. The discovery was a surprise because the AKT pathway is typically not very active in mouse models of pancreatic cancer However, most studies look only at young mice. Experimental drugs already exist that inhibit the AKT pathway. When the team tested AKT-inhibiting drugs in mouse models of pancreatic cancer, they found the drugs reduced tumor growth in mice with aged fibroblasts. However, it had no effect in mice with young fibroblasts. Researchers next plan to study age-related changes in other cells found in pancreatic cancer tumors, including immune cells, and their impact on pancreatic cancer.

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/2024/02/age-related-changes-in-fibroblast-cells-promote-pancreatic-cancer-growth-and-spread

Loss of synaptic connections between neurons is one of the harmful outcomes of neurodegenerative conditions such as Alzheimer's disease. In mouse models of Alzheimer's disease engineered to produce amyloid-β, excessive pruning of synapses is thought to be a maladaptive response to the presence of misfolded amyloid-β. Investigating the details of this excessive pruning in cell cultures, researchers have found a way to interfere in the signaling involved. At least in vitro there are positive results, but it remains to be seen as to how well this approach will work in the animal models of Alzheimer's disease.

Researchers, using rodent neurons, found that targeting a protein called Mdm2 with an experimental cancer drug known as nutlin, stopped neurotoxic amyloid-b peptides that accumulate in Alzheimer's disease (AD) from overly pruning synapses. Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus. Trimming excess dendritic spine synapses is normal in the post-natal brain but can be abnormally accelerated in AD, causing loss of memory and learning.

When this protein Mdm2 is turned on inappropriately, it leads to pruning of the synapses when amyloid-b is present. Amyloid-b is the main component of amyloid plaques found in the brain of those with AD. "When we used the drug that inhibits Mdm2 on the neurons, it completely blocked dendritic spine loss triggered by amyloid-b. So inhibiting this protein is clearly working. There are questions if anti-amyloid therapy is the be-all and end-all of AD therapy. Even if you could tolerate the high cost, the effectiveness is questionable. We are saying that it may also be possible to intervene in the process by blocking some of the impacts of amyloid-b. And you could intervene by targeting Mdm2."

Link: https://news.cuanschutz.edu/news-stories/blocking-key-protein-may-halt-progression-of-alzheimers-disease

Today I'll point out an interview with one of the Cyclarity Therapeutics founders, illustrative of the degree to which biotech companies are at the mercy of regulators once they arrive at the clinical stage of development. Cyclarity, formerly Underdog Pharmaceuticals, is a spin-out from the SENS Research Foundation, an organization that aims to clear roadblocks in the translational research needed for the production of rejuvenation therapies. The program that led to Cyclarity was focused on finding a way to clear 7-ketocholesterol from the body. 7-ketocholesterol is a form of oxidized cholesterol, created as a result of oxidative stress, and is toxic to cells. Oxidative stress rises with age, and is associated with age-related chronic inflammation, and thus a growing presence of 7-ketocholesterol begins to cause harm in the aging body.

The advance in capabilities developed by SENS Research Foundation and now Cyclarity is to alter cholesterol-binding cyclodextrin molecules to be selective for 7-ketocholesterol while leaving ordinary cholesterol alone. The company is targeting atherosclerosis, hoping to prove that clearance of 7-ketocholesterol can improve on the modest slowing of the condition produced by statin drugs. 7-ketocholesterol is thought to be relevant to the growth of atherosclerotic lesions, acting to impair the macrophages responsible for clearing excess cholesterol from blood vessel walls.

It is clearly the case that in cell culture experiments it requires less 7-ketocholesterol than cholesterol to overwhelm macrophages and cause them to become foam cells or die. The challenge for animal studies is the lack of appropriate animal models of atherosclerosis, ones that exhibit both appropriate levels of 7-ketocholesterol in addition to the development of atherosclerotic lesions. Thus Cyclarity is carrying forward into human trials as the first big proof of concept experiment beyond cells and ex vivo tissue sections.

Solving Atherosclerosis: The Small but Mighty Molecule

During the last interview we did a year or so ago, Cyclarity was preparing to enter clinical trials here in the UK. You mentioned that there were two broad categories of things that you had to do, which were the safety testing and the manufacturing process. How is it going with those two things?

They're going great. We finished the manufacturing process for the human quality drug material in what's called the Current Good Manufacturing Practice. This human-grade material is packaged and in sterile single use vials ready for patients and volunteers. We are still finishing the safety testing because we changed the formulation slightly along the road. So there's some additional, confirmatory tests that we need to do before we can get it into people. There's a lot of rules and regulations around putting new drugs into people, and so there's just a few more hoops that we need to jump through that we're finishing up in the next month or so.

While our drug isn't as cheap to manufacture as drugs like aspirin or statins, it's a lot cheaper than biologics like therapeutic antibodies or gene therapies, and we've built our drug manufacturing process to be scalable. We've already scaled that up compared to when we started out. A few years ago, we were only making a couple hundred milligrams of our drug at a time, and now we are making multiple kilograms. Our process is scalable to dozens or hundreds of kilograms at a time, and it'll get cheaper as we go. At this point, I don't think it'll ever be dirt cheap, like pennies per dose, but it should be affordable to anyone and everyone who needs it.

When we talked last time, you were poised to go into human clinical trials in Cambridge, UK, working with the Medicines and Healthcare products Regulatory Agency (MHRA). I understand the situation a year on has changed, and you've decided to launch in another location, can you tell us more?

We're continuing to engage with the MHRA. In fact, we have another scientific advice meeting in two weeks that we'll be holding virtually. We're excited to be working with the MHRA and hopefully doing part of our Phase 2 clinical trial in the UK. To remind your readers, we were one of the first recipients of the UK's ILAP program, the innovative licensing and access pathway, and that's what really brought us to the UK. In addition to the good environment there, lots of collaborators, lots of innovation happening, especially in the imaging field in the UK.

The bad thing is that post Brexit, it seems that the MHRA has gotten a bit backlogged and isn't able to keep up with our current demands on their time. It takes too long to get meetings and responses to applications currently. We've had to take our first human clinical trial to Australia, where it's a faster, more streamlined, and cheaper process. We are really excited to be working with some great people there. Steve Nichols, a world-renowned cardiologist, who we brought on as an advisor, has really helped pave the way and show us the ropes of how to navigate the system and get things going really fast in Australia. We think we'll be able to efficiently get our trial done there.

This will be a Phase 1 trial, the safety phase, right?

Yeah, we are going to have 12 patients in the second part or the third part of our Phase 1 trials. That's to make sure that it will be safe for patients, but it's also going to give us a chance to look at those patients and see if their arterial disease and other health factors improve. That will help us with the design of the Phase 2 trial. The Phase 2 trial will take longer because we have to follow up with patients a year later. That'll be a bit of a longer process, but we do hope to observe those patients and see if they start seeing some benefits.

There's a lot more money coming into the field compared to a decade ago. What do you think is now the biggest sort of barrier to progress for the field?

Well, I think it's still money, but it's money at a different stage of the game. For one thing, funding for the earlier preclinical research is a lot more plentiful than it was previously for companies, which is great. That's created an amazing ecosystem of longevity biotechnology companies, and there will be a lot of companies now, like us, translating the results from preclinical to clinical work, so we still need the money to grow with us and follow us into the clinic. That's one challenge. I think another challenge is in the regulatory realm, because if you come in and you say, "I have an anti-aging therapy", it's still tricky to figure out how to design a clinical trial around that.

So I think there's good news and bad news. I think there's plenty of room to move forward even without any new definitions of aging as a target or treating aging itself as a therapy. I think it's actually more important to change the minds of the people developing drugs, as we've been doing, by getting in there and doing it ourselves, but also getting other people who would normally be doing something a little more traditionally pharmaceutical to start thinking about it from the aging perspective and getting scientists, doctors, and regulators to be thinking in that context too.

When it comes down to picking an indication, there's so many to choose from, because most of the major diseases right now are diseases of aging, so I don't think people should get discouraged by saying, "Oh no, the bad regulators won't recognize aging as a disease, so we can't get anti-aging therapies into clinical trials". Because you can, you just need to pick one aspect of aging to focus on and measure aspects of aging in things like heart disease, dementia, lung function, and muscle function.

The balance of microbial populations making up the gut microbiome changes with age, both a loss of microbes generating beneficial metabolites and an increase in the number of inflammatory microbes. Separately from this harmful process, a number of studies have shown that that aged gut microbiome is distinctly different in patients with Alzheimer's disease, suggesting that there may be a meaningful contribution to disease onset and progression arising from the gut. The precise mechanisms involved have yet to be identified. While inflammation has an important role in Alzheimer's disease, the contribution of an Alzheimer's-like gut microbiome may not be as simple as increased levels of chronic inflammation in comparison to other older individuals.

Unlike the typical aging process, Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by a range of cognitive impairments affecting various aspects of daily life. These impairments impact memory, thinking, decision making, communication, problem solving, personality, and mobility. In AD, the formation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs) leads to inflammation and a gradual decline in cognitive function. Despite various hypotheses about the development of AD, its onset and progression remain unclear.

Recent evidence suggests that the gut microbiota-brain axis could offer insights into the early diagnosis and treatment of neurodegenerative disorders, including depression and AD. Gut health is significantly influenced by microbiota, which is largely composed of diverse microorganisms and resides primarily in the gastrointestinal tract. The gut microbiota's role in AD pathogenesis has been extensively explored, revealing that individuals with AD and mild cognitive impairment (MCI) exhibit a lower gut microbiota diversity index than healthy controls.

Additionally, studies indicate similarities in the gut microbiota of individuals with MCI and AD, offering potential insights into pre-dementia pathogenesis and the identification of at-risk individuals. Moreover, numerous studies are pursuing the goal of understanding and mitigating changeable risk factors for AD pathology, such as lifestyle, different types of dietary patterns, and obesity. These external factors play a critical role in AD development. Conversely, research has shown that a healthy diet may offer a non-pharmacotherapeutic approach to modulating AD neuropathological markers. Therefore, researchers are studying several lifestyle and dietary patterns in order to determine which patterns are most effective in preventing AD, focusing primarily on the Mediterranean diet, DASH diet, MIND diet, and ketogenic diet. Gut microbiota can be affected by several factors, including genetics, age, antibiotics, and diet. Hence, this review aims to enhance our understanding of gut microbiota function, the role of diet, and the connections of these factors to AD.

Link: https://doi.org/10.3390/nu16030412

Development of the fasting-mimicking diet resulted from efforts to find out where the beneficial response to fasting begins; how much can one eat and still be effectively fasting? Where is the trigger point? An individual can in fact gain a majority of the benefits of fasting at around 600 calories per day, and five days of fasting mimicking produces beneficial changes in metabolism that can last for months. A formal fasting mimicking diet was created has undergone clinical trials as an adjuvant therapy in the treatment of cancer. In practice fasting mimicking is easily carried out at home without the formal diet: count calories, eat sensibly. Here, researchers show that Klemera-Doubal biological age is lowered by a few years following fasting mimicking, alongside a measure of immune system aging, an interesting result.

In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we test the hypothesis that FMD cycles improve the levels of multiple markers of aging thus reducing biological age as measured by a set of validated blood markers and by other cellular and metabolic measurements. We report on the secondary outcome measures of the FMD-trial (NCT02158897) which are biomarkers associated with aging or age-related diseases, and metabolic syndrome, including visceral and hepatic fat, lymphoid/myeloid ratios, and blood markers, which were not investigated in the original report.

We show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging), and increased lymphoid to myeloid ratio, an indicator of immune system age. Based on the Klemera-Doubal measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.

Link: https://doi.org/10.1038/s41467-024-45260-9

Average telomere length in a tissue is some reflection of (a) stem cell activity and (b) pace of cell division. Telomeres, repeated DNA sequences at the ends of chromosomes, lose some of their length with each cell division, and cells self-destruct or become senescent when telomeres become too short. This limits the ability of somatic cells to replicate, reducing the odds that a given cell will mutate to become cancerous by imposing a limit on cell activity and cell life span, enforcing turnover of cells in tissues. Stem cells, in comparison, are a small, well protected, privileged set of cell populations that use telomerase to extend their telomeres after cell division. Stem cells produce daughter somatic cells with long telomeres to replace those lost to telomere shortening and other wear and tear.

Since stem cell activity declines with age, and damage and cell stress increases in somatic cell populations, the average length of telomeres tends to decline with age. This relationship needs a large study population to appear; individuals are highly variable. Nonetheless, this was one of the first possible measures of biological age to arise from the research community, and was greeted with some excitement for a time.

While the research and development communities are just as subject to fashion and mania as every other human endeavor, the focus of discussion moving over time from topic to topic, it is important to remember that this doesn't change the underlying science. Telomere length was hot for a while, and now it is not, but the pros and cons regarding induction of telomere lengthening as a mode of therapy remains much the same. The only difference these days is that some few people are actually undergoing telomerase gene therapy in a limited way via medical tourism; no data is published on that, of course. Small formal clinical trials are closer at hand, but still a work in progress.

Unlocking longevity: the role of telomeres and its targeting interventions

Telomere attrition belongs to the cardinal hallmarks of aging and has garnered significant attention in gerontological research over the past years. Targeting telomere dynamics presents a promising avenue in gerontology, well-aging, and the development of therapies for age-associated ailments, underlining the importance of understanding telomere dynamics. Despite telomeres' established role in aging, the field of telomere biology faces a significant challenge: the lack of effective, clinically proven therapies that directly target telomeres. This gap underscores the complexity of translating fundamental telomere research into therapeutic applications and the challenges in addressing the multifaceted nature of telomere dynamics and their systemic impact on aging and age-related diseases. Therefore, continued exploration and innovative strategies in telomere research are essential to develop tangible, effective treatments for age-related pathologies.

Telomere dysfunction intensifies the molecular hallmarks of aging, potentially amplifying age-related diseases like neurodegeneration and cancer; conversely, the profound understanding of its underlying mechanisms offers avenues for mitigating aging and its associated disorders. The maintenance of telomere length, either through genetic interventions or modulating telomerase activity, has been shown to delay cellular aging and extend the healthspan in various model organisms. Experimental elongation of telomeres through genetic manipulation or pharmacological means has already shown potential in delaying cellular and tissue aging, suggesting an avenue for therapeutic interventions by targeting the aging process itself.

Telomerase gene therapy is an emerging approach that seeks to address cellular aging by directly modulating telomerase activity in cells. In an in vivo study conducted in mice, telomerase gene therapy using an adeno-associated virus to express TERT led to significant health improvements and reduced aging markers without elevating cancer incidence. Remarkably, the treatment extended the median lifespan by 24% in 1-year-old mice and 13% in 2-year-old subjects, underscoring the potential of TERT-focused interventions in aging mitigation. Another study in a mouse model investigated the therapeutic potential of telomerase gene therapy using adeno-associated virus 9 (AAV) gene vectors to treat aplastic anemia, which is associated with telomere shortening. AAV9-Tert effectively targeted the bone marrow, lengthened telomeres, and mitigated the symptoms of the disease. An in vivo study investigated the influence of telomere length on health in mice derived from embryonic stem cells with hyper-long telomeres. The mice with hyper-long telomeres exhibited reduced DNA damage with aging, improved metabolic markers such as lower LDL levels, improved glucose and insulin tolerance, decreased cancer incidence, and increased longevity.

Certainly, direct telomerase gene therapy has not been more than tentatively tested in humans due to safety and ethical concerns, unknown long-term effects, and the technically challenging delivering mechanism. Nevertheless, abandoning the telomerase gene therapy approach may be premature given its potential to revolutionize aging and disease treatment. The challenges in human translation certainly necessitate refined methodologies and advanced clinical trials to bridge the gap, ensuring the approach's safety and efficacy for human therapeutics.

Leucine is an essential amino acid, only obtained from the diet rather than synthesized by our cells. Leucine supplementation has been proposed as a way to slow the loss of muscle mass with age, as leucine processing becomes dysregulated with aging in a way that can be compensated for by adding more leucine to the diet. Whether this actually works is a matter for debate; the evidence is mixed. The question is never whether the mechanism exists, the question is whether it has a large enough effect size to matter.

Given this impetus for a greater intake of dietary leucine in later life, it is interesting to see the research noted here, in which higher dietary protein intake, and particularly leucine, is shown to accelerate atherosclerosis via effects on the behavior of macrophage cells. In the bigger picture, reduced protein intake slows aging, through methionine seems more important than leucine when it comes to triggering beneficial mechanisms based on nutrient sensing. One is left to consider these various opposing points of view, and look forward to a future of rejuvenation therapies that produce large enough reversals of degenerative aging make all of these present dietary considerations irrelevant.

Following 2020 research, in which scientists first showed that excess dietary protein increases atherosclerosis risk in mice, the next study conducted by this group delved deeper into the potential mechanism and its relevance to the human body. "We have shown in our mechanistic studies that amino acids, which are really the building blocks of the protein, can trigger disease through specific signaling mechanisms and then also alter the metabolism of these cells. For instance, small immune cells in the vasculature called macrophages can trigger the development of atherosclerosis."

Based on initial experiments in healthy human subjects to determine the timeline of immune cell activation following ingestion of protein-enriched meals, the researchers simulated similar conditions in mice and in human macrophages, immune cells that are shown to be particularly sensitive to amino acids derived from protein. Their work showed that consuming more than 22% of daily dietary calories through protein can negatively affect macrophages that are responsible for clearing out cellular debris, leading to the accumulation of a "graveyard" of those cells inside the vessel walls and worsening of atherosclerotic plaques overtime. Interestingly, the analysis of circulating amino acids showed that leucine - an amino acid enriched in animal-derived foods like beef, eggs and milk - is primarily responsible for abnormal macrophage activation and atherosclerosis risk.

"Perhaps blindly increasing protein load is wrong. Instead, it's important to look at the diet as a whole and suggest balanced meals that won't inadvertently exacerbate cardiovascular conditions, especially in people at risk of heart disease and vessel disorders." Researchers also notes that these findings suggest differences in leucine levels between diets enriched in plant and animal protein might explain the differences in their effect on cardiovascular and metabolic health.

Link: https://www.eurekalert.org/news-releases/1034427

Here researchers provide another data point for the ongoing debate over whether and how persistent viral infection contributes to neurodegeneration. The data is mixed to date, with some studies showing correlation and some not. Some research shows ongoing antiviral drug treatment to correlate to a lower risk of neurodegeneration, while others (such as the work here) do not. Other research suggests that interactions between several different persistent viruses may be required, but this remains a recent discovery and yet to be confirmed. This part of the field is a work in progress: some suggestive data, some contradictory data, a few possible explanations, but no firm conclusion as of yet. Still, the cost-benefit calculation for taking antiviral drugs in later life looks good; they are not that expensive, and a person only has the one brain.

The relationship between herpes simplex virus (HSV) and dementia has not been elucidated fully and results obtained to date are far from unanimous. To better understand the potential effects of HSV on incident Alzheimer's disease (AD) or dementia, suspected interactions with common co-infections, their treatment, and risk-related genes need to be considered in analyses, which has not commonly been reported together. Further, age is the strongest risk factor for dementia, which is difficult to adequately adjust for. The aim of this study was to investigate the roles of HSV, HSV-1 specifically, and cytomegalovirus (CMV) in AD and dementia risk, including examination of potential interactions with APOE ɛ4 carriership and the effects of anti-herpesvirus treatment, in a prospective cohort of same-age individuals.

This study was conducted with 1,002 dementia-free 70-year-olds living in Sweden in 2001-2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-CMV IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical records. Cox proportional-hazards regression models were applied.

Cumulative AD and all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and anti-CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE ɛ4 or anti-CMV IgG. Similar results were obtained for HSV-1. In conclusion, HSV (but not CMV) infection may be indicative of doubled dementia risk.

Link: https://doi.org/10.3233/JAD-230718

The state of anti-viral therapies isn't that great, all things considered. Technology has not yet advanced to the point at which a viral infection can be simply shut down, as is the case for near all bacterial infections. The present anti-viral drugs are either vaccines (useful!) or merely shift the odds somewhat by interfering in some part of the viral life cycle, but nowhere near as effectively as desired. Many persistent viral infections are thought to contribute meaningfully to forms of age-related dysfunction, and there is too little that can be done about that at the present time.

This landscape is one of the reasons why there was so much interest in our community in the double-stranded RNA activated caspase oligomerizer (DRACO) technology, an approach to selectively killing cells in which viral replication is taking place. DRACO offered the promise of being broadly and rapidly effective for ending infection by many different viruses, and doing so with little adaptation of the core technology from virus to virus, a big improvement over the present state of the art. Initial results in animal studies looked good.

As is all too often the case for promising technologies, however, the DRACO research program faltered in funding and ultimately halted. It took some time, and a number of failed fundraising efforts, for another group to emerge to pick up the flag and run with it. That group is Kimer Med, a New Zealand biotech startup. It seems they have made considerable strides in the last few years, building their own version of DRACO without the assistance of the original researchers, and improving on the technology to the point at which clinical trials are foreseeable.

What happened to DRACO?

When Dr Todd Rider announced his breakthrough DRACO discovery in 2011, the world sat up and took notice. Headlines read: "Experimental drug could defeat any virus", and "A kill switch for all viruses". Rider's discovery was called "visionary" by the White House and named one of the best inventions of the year by Time magazine. But then, nothing happened. Rider lost his funding. He tried crowdfunding and failed, and very little has been heard of him and his revolutionary discovery since.

Enter Kimer Med

Kimer Med was founded in March 2020 during the height of the COVID-19 pandemic. The founders both knew of Rider's work and understood its potential, but were surprised to find that it had not progressed further, especially given the obvious need. With decades of scientific and entrepreneurial experience between them, they founded Kimer Med to pursue the life-saving promise of broad-spectrum antivirals. However, the journey has not been easy. Both Rider's DRACO paper and the associated patents omitted key information, probably intentionally. It took Kimer Med two years and millions of dollars to unpack Rider's results and fill in the gaps.

But as a result of this research, Kimer Med has been able to refine and build on the foundational science, surpassing Rider's results against human viruses. Recently, the company announced success against a total of 10 different viruses, including all four serotypes of Dengue, Zika, Rhinovirus, Influenza, and HSV-2. Going one step further, Kimer Med has now designed a platform for the rapid development of modular, broad-spectrum antivirals. Using the platform, the company has been able to produce and test a wide range of antiviral compounds. The good news is, based on their antiviral's mechanism of action and the ability to customise antivirals to bypass viral defences, Kimer Med believes that efficacy is likely against many more viruses, as well as new, as-yet-unknown viruses ("disease X").

Does this mean we can cure just about any viral infection?

The initial promise of DRACO was "kryptonite for viruses" - one miracle therapy that could wipe out all viral infection. "Based on our research over the past three years, we don't think that's probable. What is possible, and very much within our reach, is a family of broad-spectrum antivirals, each one capable of treating a group of viruses. For example, our lead candidate works against Dengue and Zika virus, both members of the flavivirus family, and we expect that we'll see results against some other flaviviruses as well."

The implications for human health and longevity

There are currently about 220 viruses known to infect humans, resulting all manner of disease, as well as causing or contributing to many other conditions such as Alzheimer's Disease, multiple sclerosis, and multiple forms of cancer. Numerous latent viruses infect vast numbers of the human population, and are linked to deterioration and dysfunction of the immune system - immunosenescence - which results in increased vulnerability to infection and sickness as we age. Right now, there are approved antiviral treatments for only 11 of these 220 viruses.

Most current antiviral therapies merely suppress or inhibit viral replication. Curative antivirals are scarce, and there's no existing treatment that can eradicate latent infection. One of the potential advantages of Kimer Med's antivirals is that they bolster the innate immune system, helping it eliminate virally infected cells. Instead of bursting open and spreading the virus throughout the body, infected cells are disposed of by triggering a natural process known as apoptosis - the orderly breakdown and disposal of damaged, infected or unwanted cells.

"Despite decades of antiviral development, we really haven't seen anywhere near the same success against viruses as we saw with early antibiotics, such as penicillin and sulfa. Rider's great insight was to target the dsRNA common to virtually all viruses, instead of something highly specific, which is what most conventional antivirals do. This has opened the door to genuinely broad-spectrum antivirals, and paved the way for us to create therapies for a whole range of currently unmet medical needs. Our goal now is to complete our pre-clinical studies and progress our first antiviral through to phase one clinical trials. Ultimately, this is where Rider failed and where we must now succeed."

Here, researchers investigate correlations between late life mortality and levels of specific proteins produced by senescent cells as a part of the senescence-associated secretory phenotype (SASP). While looking over the paper, it is worth bearing in mind that circulating levels of many of the molecules thought to be important components of the SASP do not appear to correlate well with senescent cell burden. Why this is the case remains to be understood on a molecule by molecule basis, but note that many of the SASP molecules are widely used for signaling by other cell types and in other circumstances.

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults.

We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1,923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79) than the covariates alone (0.70). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.

Link: https://doi.org/10.1111/acel.14006

It is not always the case that genetic alterations that shorten life span are interesting: there are many ways to break a complex system, and only some of those breakages are relevant to the dysfunction of aging. Researchers here explore the transfer of RNA between cells in nematode worms, showing that too much RNA uptake causes reduced life span. Is this relevant to aging, however? Most likely only if this set of regulatory processes become changed in maladaptive ways in later life. Otherwise, this is just another one of the countless different ways to break the complex regulatory systems of a living organism.

Intertissue RNA transport recently emerged as a novel signaling mechanism. In mammals, mounting evidence suggests that small RNA transfer between cells is widespread and used in various physiological contexts. In the nematode C. elegans, a similar mechanism is conferred by the systemic RNAi pathway. Members of the Systemic RNA Interference Defective (SID) family act at different steps of cellular RNA uptake and export.

The limiting step in systemic RNA interference (RNAi) is the import of extracellular RNAs via the conserved double-stranded RNA (dsRNA)-gated channel SID-1. To better understand the role of RNAs as intertissue signaling molecules, we modified the function of SID-1 in specific tissues of C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in C. elegans intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were attenuated by silencing the components of systemic RNAi sid-1, sid-2 and sid-5, implicating systemic RNA signaling in the lifespan reduction. Accordingly, tissue-specific overexpression of sid-2 and sid-5 also reduced worm lifespan.

Additionally, an RNAi screen for components of several non-coding RNA pathways revealed that silencing the miRNA biogenesis proteins PASH-1 and DCR-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Collectively, our data support the notion that systemic RNA signaling must be tightly regulated, and unbalancing that process provokes a reduction in lifespan.

Link: https://doi.org/10.1016/j.gene.2023.148014

The largest of the present challenges facing the use of epigenetic clocks to measure biological age is that there is no established causal connection between what the clock measures, meaning the methylation status of specific CpG sites on the genome, and specific aspects of the burden of age-related damage and dysfunction; e.g. which changes are due to chronic inflammation, which due to mitochondrial dysfunction, etc. Thus the results obtained from an epigenetic clock assay, the raw methylation data or the resulting epigenetic age, are not actionable. There is nothing one can do with that information to guide health practices or choice of intervention.

Various approaches are under development to attempt to connect DNA methylation of CpG sites to underlying mechanisms of aging. The slow and painful method is to investigate each CpG site in isolation, and this has the look of decades of work at the very least. There are other ways forward, however. The one noted here is a clever use of Mendelian randomization to try to link CpG sites to observable traits, followed by splitting up clocks into (probably) harmful methylation changes versus (probably) adaptive methylation changes. Given that as a tool, then one can try to validate whether this assignment of harmful versus adaptive methylation changes is any good using independent data sets and animal studies.

New epigenetic clocks reinvent how we measure age

Existing epigenetic clocks predict biological age (the actual age of our cells rather than chronological) using DNA methylation patterns. However, until now, no existing clocks have distinguished between methylation differences that cause biological aging and those simply correlated with the aging process.

Using a large genetic data set, researchers performed an epigenome-wide Mendelian Randomization (EWMR), a technique used to randomize data and establish causation between DNA structure and observable traits, on 20,509 CpG sites causal to eight aging-related characteristics. The eight aging-related traits included lifespan, extreme longevity (defined as survival beyond the 90th percentile), health span (age at first incidence of major age-related disease), frailty index (a measure of one's frailty based on the accumulation of health deficits during their lifespan), self-rated health, and three broad aging-related measurements incorporating family history, socioeconomic status, and other health factors.

With these traits and their associated DNA sites in mind, researchers created three models, termed CausAge, a general clock that predicts biological age based on causal DNA factors, and DamAge and AdaptAge, which include only damaging or protective changes. Investigators then analyzed blood samples from 7,036 individuals ages 18 to 93 years old from the "Generation Scotland Cohort" and ultimately trained their model on data from 2,664 individuals in the cohort. With this data, researchers developed a map pinpointing human CpG sites that cause biological aging. This map allows researchers to identify biomarkers causative to aging and evaluate how different interventions promote longevity or accelerate aging.

Causality-enriched epigenetic age uncouples damage and adaptation

Machine learning models based on DNA methylation data can predict biological age but often lack causal insights. By harnessing large-scale genetic data through epigenome-wide Mendelian randomization, we identified CpG sites potentially causal for aging-related traits. Neither the existing epigenetic clocks nor age-related differential DNA methylation are enriched in these sites. These CpGs include sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits.

We established a new framework to introduce causal information into epigenetic clocks, resulting in DamAge and AdaptAge-clocks that track detrimental and adaptive methylation changes, respectively. DamAge correlates with adverse outcomes, including mortality, while AdaptAge is associated with beneficial adaptations. These causality-enriched clocks exhibit sensitivity to short-term interventions. Our findings provide a detailed landscape of CpG sites with putative causal links to lifespan and healthspan, facilitating the development of aging biomarkers, assessing interventions, and studying reversibility of age-associated changes.

MTTP is a longevity-associated gene involved in lipid metabolism and correlated with cardiovascular function. Here, researchers use flies to demonstrate that the fly version of MTTP, called mtp, is involved in the mechanisms by which exercise improves long-term cardiac health. It isn't clear as to how exactly MTTP or mtp is involved in the known set of mechanisms important to the pace of aging and cardiovascular health. That sort of deep dive into establishing connections between cellular processes occurs only after numerous studies have demonstrated an interesting correlation, and even then it is a slow and incremental process.

Microsomal triglyceride transfer protein (mtp) in Drosophila is a direct homolog of human MTTP (microsomal triglyceride transfer protein), a lipid transfer protein found in the liver and intestine. Given its role as a rate-limiting enzyme in lipid metabolism, MTP has been associated with human longevity, coronary artery disease, and other vascular diseases caused by adverse lipid profiles (peripheral vascular disease, renal vascular disease, and stroke), which account for a significant portion of human mortality.

Diastolic dysfunction is a major cardiac dysfunction, and an important predisposing factor is age. Although exercise training is often used for the prevention and treatment of cardiovascular disease nowadays, little is currently known about whether exercise interventions associated with the slowing of cardiac aging are related to mtp-related pathways.

In the present study, after establishing a Drosophila exercise model, we found that cardiac systolic function and mtp expression levels decline with aging in Drosophila. Besides, there is a strong association between age-related diastolic dysfunction and mtp expression levels. Importantly, endurance exercise improves age-related diastolic dysfunction and prolongs lifespan, possibly related to the upregulation of mtp expression, thereby enhancing lipid metabolism in aged Drosophila.

Link: https://doi.org/10.14814/phy2.15929

A fair amount of the research and development work aimed at spurring greater regeneration of an injured heart is focused on cardiomyocytes, either by delivering new cells, or by encouraging existing cells to replicate or otherwise better resist the hostile environment following injury. As researchers here point out, regeneration is known to be an intricate dance between multiple different cell populations. Thus the signaling that facilitates coordination between those cell types may prove to be a better target for intervention than any single cell population, and single cell population approaches that have shown promise in the past may be promising because they indirectly stimulate the right sort of signaling in the injured heart.

Intensive investigations utilizing single-cell genomics and genetic experiments were conducted by a team of scientists to shed light on the potential of the human heart to achieve self-repair and regeneration. Heart disease remains a leading cause of death worldwide, with myocardial infarction, also known as a heart attack, causing irreparable damage to cardiac muscle cells. While current treatments focus on alleviating symptoms and improving blood flow, they fall short in addressing the crucial issue of lost cardiomyocytes (CMs), leading to further complications such as heart failure.

Contrary to longstanding beliefs, the study reveals that regeneration of CMs requires a complex microenvironment, where a dynamic synergy between CMs, resident immune cells, and cardiac fibroblasts is the driving force behind cardiac renewal. Through intricate signaling mechanisms, these cell types coordinately instruct and support each other, facilitating CM proliferation and effectively repairing damaged heart tissue. "Understanding heart regeneration on a molecular level is an important step towards developing innovative therapeutics that can facilitate CM regeneration. Our study challenges the existing paradigm, suggesting that targeting the microenvironment rather than a specific cell type is instrumental in healing the injured heart."

Link: https://www.texasheart.org/targeting-the-microenvironment-rather-than-a-specific-cell-type-could-be-the-key-to-healing-injured-hearts/

There are presently two views of the way in which stochastic DNA damage can contribute to aging. Most DNA damage occurs in inactive genes in cells that will not replicate many more times, and thus cannot possibly produce systemic consequences throughout large regions of the body. The first argument for a way in which random DNA damage can produce a broader effect is via somatic mosaicism, in which mutational damage occurs in stem cells, allowing those mutations to spread throughout tissue over time. It is unclear as to how to measure the contribution of this process to age-related loss of function, however, and its contribution to aspects of aging other than cancer risk remains debated.

The second view focuses on changes in gene expression that can result from the complex processes of DNA damage and DNA repair. The actions of DNA repair in particular can alter the balance of various factors in the cell nucleus, leading to altered epigenetic marks on the genome, altered nuclear genome structure, and consequently altered transcription of DNA to RNA. This can link DNA damage even in inactive genes to broad consequences for cell behavior. Today's popular science article provides a readable overview of one such issue noted in older animals, dysfunction in the RNA polymerase II that moves along the genome to read DNA and assemble molecules to form RNA. With age, this production of RNA becomes slower and more prone to failure, changing the landscape of gene expression and thus also changing cell behavior.

Why Do We Age? DNA Damage A Likely Cause

Researchers discovered that, in older mice, RNA polymerase II often begins to stall while transcribing DNA into RNA. By analyzing the liver of two-year-old mice - ancient, by mice standards - they noticed that up to 40% of all RNA polymerase II complexes had stalled. To add to this, each stalled complex is likely to block the next three complexes behind it, quickly leading to queuing and gunking up the DNA strand until the obstruction can be cleared. The researchers found that larger genes are especially prone to these issues, leading to a bias towards expression of small genes.

With transcription interrupted, gene expression is also interrupted. As a result, many cellular pathways begin to go haywire; they are deprived of the proteins they need for problem-free functioning. These include all of the same pathways that begin to malfunction as we age. In other words, the genetic fingerprint produced by interrupted transcription is the same as that produced by aging, suggesting that the two are intimately connected. Affected pathways include those involved in nutrient sensing, clearing of cellular debris, energy metabolism, immune function, and the ability of cells to handle damage. All of these play vital roles in shaping life span.

The researchers next set out to understand what caused the RNA polymerase II to stall in older mice. Their suspicions fell on spontaneous, internal DNA damage. Gene expression patterns in cells that have been exposed to DNA-damaging agents are very similar to those seen during normal aging. Premature aging disorders, such as Cockayne syndrome, are also characterized by DNA damage; the usual DNA repair mechanisms malfunction, leading to stalled RNA polymerases at sites of damage, known as lesions. Given these similarities, the scientists speculated that DNA damage could also be involved in normal aging.

To test their hunch, the researchers monitored genetically altered mice that lacked the usual DNA repair machinery, leaving them prone to accumulated DNA damage. These mice exhibit many features of premature aging, including a significantly shortened lifespan. As expected, the rate of transcription was noticeably lower in these mice compared to healthy controls.

Researchers here demonstrate an association between increased claudin-5 levels in the bloodstream and age-related neurodegeneration. This is distinct from an underlying age-related decline in claudin-5 levels. The scientists do not speculate too deeply as to why this relationship might exist, but others have done so in the past. In short, claudin-5 is an important tight junction protein in the blood-brain barrier wrapping blood vessels that pass through the central nervous system. The blood-brain barrier prevents unwanted molecules and cells from passing to and from the brain. Dysfunction and leakage of the blood-brain barrier is characteristic of later life and neurodegenerative conditions, encouraging inflammation in brain tissue in response.

While claudin-5 is clearly necessary for blood-brain barrier function, it is an open question as to why exactly there is more of it in the bloodstream in the context of outright neurodegenerative disease versus the context of aging. Is some other form of disarray preventing it from integrating into the barrier when expressed, or is upregulation of expression a response to dysfunction in the blood-brain barrier, or is some other process at work under the hood?

The blood-brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). Claudin-5 (CLDN-5) is a protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL).

The BBB functions as a selective gate for the uptake of essential molecules from blood into the brain and the excretion of harmful molecules from the brain into blood via transporters and receptors on cellular membranes. In addition, the BBB prevents the influx of blood-borne neurotoxins, cells, and pathogens into the brain because of the formation of tight junctions (TJs) in the intercellular space between adjacent macrovascular endothelial cells. Loss of BBB integrity has been observed in neuroinflammatory disorders, and patients with early AD demonstrate BBB leakage. In addition, patients with early cognitive dysfunction show BBB breakdown in the hippocampus, which occurs independently of brain accumulation of amyloid and tau. These several findings indicate that BBB TJ-sealing components might be impaired in MCI- and AD-related pathology.

Breakdown of the BBB, which is associated with CNS diseases, is accompanied by the invasion of leukocytes and activation of astrocytes. The matrix metalloproteinases (MMPs) secreted by these invading leukocytes have been shown to lead to the degradation of CLDN-5 in the BBB of mice. In a rat ischemic model, MMPs secreted from astrocytes likewise degraded CLDN-5 in the BBB. In addition, the number of pericytes in the BBB was greater in patients with AD compared with cognitively healthy peers, perhaps reflecting a response to endothelial breakdown. As is similar to our findings for patients with MCI or AD, circulating CLDN-5 levels are elevated in other CNS diseases, including ischemic stroke, bipolar disorder, and obsessive-compulsive disorder. The CLDN-5 circulating in blood might be derived from the endothelial cells in the BBB.

Interestingly, we found a significant negative association of plasma CLDN-5 level with age in MCI and AD. Ultrastructural analysis of TJ seals in the BBB did not reveal normal age-associated changes. In the current study, CLDN-5 levels were higher in younger than in older patients in both the MCI and AD groups. This is consistent with an analysis of autopsied brains which reported that the CLDN-5 level decreases with AD progression. Because reactive astrocytes and endothelial cells in the BBB in AD produce MMPs, prolonged activation of MMPs might lead to the degradation of CLDN-5 and, thus, lower plasma CLDN-5 levels in older compared with younger patients with cognitive deficits.

Link: https://doi.org/10.3390/ijms25031419

Researchers have developed a gene therapy that upregulates of Cdk1 and Cdk4 in heart muscle. These genes provoke cardiomyocytes into replication, and this has been shown to improve function in the context of heart failure. Here, researchers show that this can help to improve heart function even comparatively late into the development of progressive heart failure, broadening the number of patients who can potentially benefit once this reaches the clinic.

Heart failure remains the leading cause of mortality in the U.S. During a heart attack blood stops flowing into the heart. Without oxygen, part of the heart muscle dies. The heart muscle does not regenerate, instead it replaces dead tissue with a scar made of cells called fibroblasts that do not help the heart pump. If there is too much scarring, the heart progressively enlarges, or dilates, weakens and eventually stops working.

In a previous study, researchers successfully used gene therapy to improve acute cardiac dysfunction in animals. Their method effectively and specifically delivered genes that promote proliferation to heart cells, generating new heart muscle. This approach not only strengthened the heart improving its ability to keep the blood flowing, but also prevented typical subsequent congestion in the liver, kidneys, and lungs in rats and pigs. "In this study, we did something that had not been done before. We intervened with the same gene therapy but not during acute heart failure or early in the disease as in our previous experiments, but late in the disease during the chronic phase four weeks after cardiac injury had severely damaged the heart."

Four months after treating the animals, the researchers checked cardiac function and heart structure. "We were surprised to see evidence of significant heart cell proliferation, a marked reduction in scar size and a significant improvement in cardiac function. Although heart dilation and lung congestion associated with chronic heart failure were not improved, the treatment partially improved liver and kidney functionality."

Link: https://blogs.bcm.edu/2024/02/13/from-the-labs-not-too-late-to-repair-gene-therapy-improves-advanced-heart-failure-in-animal-model/

Glial fibrillary acidic protein (GFAP) consistently shows up in proteomic analyses of age-related neurodegenerative processes, particularly now that more research groups are engaged in building early warning biomarker profiles for the later development of Alzheimer's disease. Such studies are usually focused on Alzheimer's disease because that is where most neuroscience funding is directed, but the presence of GFAP as a marker is more generally applicable to the aging of the brain and its supporting cell populations.

Astrocyte cells exhibit increased expression of GFAP when they become reactive, it is a well-known marker of this state. Reactivity occurs in response to damage and altered signaling in the tissue environment characteristic of blood-brain barrier disruption, injury, and neurodegenerative disease. The reactivity of astrocytes is straightforward to describe, in terms of changed expression of markers and changed morphology, but the consequences of reactivity are far from fully mapped at the detail level. Reactivity may overlap with cellular senescence, but not all reactive astrocytes are senescent. The presence of reactive astrocytes is clearly associated with the progression of neurodegenerative conditions, however.

Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer's disease

Defining the progression of blood biomarkers of Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD symptoms in participants in the Baltimore Longitudinal Study of Aging. We show that increased astrocyte reactivity, assessed by elevated glial fibrillary acidic protein (GFAP) levels is an early event in the progression of blood biomarker changes in preclinical AD.

In AD-converters who are initially cognitively unimpaired (N=158, 377 serial plasma samples), higher plasma GFAP levels are observed as early as 10-years prior to the onset of cognitive impairment due to incident AD compared to individuals who remain cognitively unimpaired (N=160, 379 serial plasma samples). Plasma GFAP levels in AD-converters remain elevated 5-years prior to and coincident with the onset of cognitive impairment due to AD. In participants with neuropathologically confirmed AD, plasma GFAP levels are elevated relative to cognitively normal individuals and intermediate in those who remain cognitively unimpaired despite significant AD pathology (asymptomatic AD).

Higher plasma GFAP levels at death are associated with greater severity of both neuritic plaques and neurofibrillary tangles. In the 5XFAD transgenic mouse model of AD, we observed greater GFAP levels in the cortex and hippocampus of transgenic mice relative to wild-type prior to the development of cognitive impairment. Reactive astrocytosis, an established biological response to neuronal injury, may be an early initiator of AD pathogenesis and a promising therapeutic target.

Modern studies of the effects of excess body weight on long term health use measures, such as waist circumference or weight-adjusted waist index, that are more sensitive to visceral fat than subcutaneous fat. Excess visceral fat in the abdomen is actively harmful, in large part via causing an increased level of chronic inflammation via a variety of distinct mechanisms. Chronic inflammation accelerates the onset and drives the progression of neurodegenerative conditions, and thus might be expected to correlate with cognitive decline.

Some studies suggest that excessive obesity can lead to cognitive decline and dementia. In the relation between obesity and low cognitive performance, the area of distribution of obesity (e.g., central or overall) may be important. However, some common obesity measurement indices, like body mass index (BMI), lack sensitivity in identifying body fat distribution. Based on this, a new index for assessing obesity called the WWI (weight-adjusted waist index), has been proposed to evaluate obesity by weight-standardized waist circumference. The WWI can reflect weight-independent central obesity and has better accuracy than BMI.

A cross-sectional research study was carried out with information from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. This research looked at the connection between the WWI and three tests of low cognitive function in US civilians. In this cross-sectional study which recruited 2,762 individuals aged 60 years and over, the authors found a marked correlation between the WWI and low cognition, and this correlation was not significantly dependent on age, sex, race, education, BMI, smoke, drink, hypertension, or diabetes. In a model with all adjustments, a positive relationship was found between the WWI and poor cognitive function.

Link: https://doi.org/10.1007/s40520-023-02649-8

Researchers here demonstrate a predictive biomarker panel for Alzheimer's disease risk based on protein levels assessed in a blood sample. This is a one of a number of similar tests developed in recent years. The question is what one might do given a measurement that suggests high risk of Alzheimer's disease. At present, the only option is to generally improve lifestyle choices, but Alzheimer's is not as correlated with lifestyle factors as is the case for, say, type 2 diabetes. Based on the suggestion that senescent cells are important to neurodegeneration, one might take senolytic drugs intermittently, a few times a year at most. Based on the evidence for persistent viral infection to be important to the development of Alzheimer's disease, one might choose to take antiviral drugs. Other options are thin on the ground at present.

Scientists used the largest cohort of blood proteomics and dementia to date, including blood samples from 52,645 healthy participants recruited from UK Biobank - a population-based study cohort. Blood samples collected between 2006 and 2010 were frozen and then analysed 10-15 years later by the research team who analysed them between April 2021 and February 2022. Until March 2023, a total of 1,417 participants went on to develop dementia - and these people's blood showed dysregulation of protein biomarkers.

Of 1,463 proteins analysed, aided by with a type of artificial intelligence known as machine learning, 11 proteins were identified and combined as a protein panel, which the researchers have shown to be highly accurate at predicting future dementia. Further incorporation of conventional risk factors of age, sex, education level and genetics, showed for the first time the high accuracy of the predictive model, indicating its potential future use in community-based dementia screening programs.

Proteins (for example Glial Fibrillary acidic protein, GFAP) had previously been identified as potential biomarkers for dementia in smaller studies, but this new research was much larger and conducted over several years. Known as a longitudinal analysis (a study conducted on a sample of participants over a number of years), the researchers were able to show the differences and trajectories between those with dementia and controls across 15 years.

Link: https://warwick.ac.uk/newsandevents/pressreleases/?newsItem=8a17841a8d79730b018d9e2bbb0e054b

Here find an interesting commentary on what might be gleaned of the prevalence of Alzheimer's disease in antiquity from the body of ancient writings on the topic of aging, memory, and health. The consensus is that Alzheimer's disease is a creation of modernity, some combination of a longer life expectancy for a greater fraction of the population coupled with increased calorie intake and less active lives. Yet unlike type 2 diabetes, risk of Alzheimer's risk doesn't correlate well with the usual suspect lifestyle choices that raise the risk of age-related disease and lower life expectancy.

This line of thinking has led to many hypotheses on the contributing factors leading to Alzheimer's disease. Some are unsupported by anything other than coincidence, comparing the introduction of a new factor in modern lives with the rising incidence of Alzheimer's disease, such as the thought that paracetamol use is causing this form of neurodegeneration. Better supported by the evidence is the view that persistent viral infection is involved in the pathogenesis of Alzheimer's disease. Since viruses evolve rapidly over time, it is tempting to speculate on the role of this viral evolution in an increased burden of Alzheimer's in the aged population today - but this is indeed only speculation. It is also hard to reconcile this hypothesis with the relative lack of Alzheimer's disease in modern hunter-gatherer populations.

Did the ancient Greeks and Romans experience Alzheimer's?

You might think age-related dementia has been with us all along, stretching back to the ancient world. But a new analysis of classical Greek and Roman medical texts suggests that severe memory loss - occurring at epidemic levels today - was extremely rare 2,000 to 2,500 years ago, in the time of Aristotle, Galen, and Pliny the Elder. Ancient Greeks recognized that aging commonly brought memory issues we would recognize as mild cognitive impairment, or MCI, but nothing approaching a major loss of memory, speech and reasoning as caused by Alzheimer's and other types of dementia. Centuries later in ancient Rome, a few mentions crop up. Galen remarks that at the age of 80, some elderly begin to have difficulty learning new things. Pliny the Elder notes that the senator and famous orator Valerius Messalla Corvinus forgot his own name. Cicero prudently observed that "elderly silliness ... is characteristic of irresponsible old men, but not of all old men."

Dementia in the Ancient Greco-Roman World Was Minimally Mentioned

The possibility that Alzheimer's disease and related dementias (ADRD) is a modern disease arises from the minimal mention of advanced cognitive decline by ancient Greeks and Romans, who were mainly concerned with the physical frailties of older ages. Because standard medical histories of elderly health lacked mention of cognitive decline, we examined texts by Greek and Roman authors that mentioned memory loss and dementia. Primary texts of Greco-Roman authors, 8th century BCE into the 3rd century CE, that mentioned cognitive decline were identified and critically evaluated. Secondary sources were excluded.

No ancient account of cognitive loss is equivalent to modern clinical data. The term dementia was occasionally used in antiquity, but not invariably linked to old age. Ancient Greeks and Romans expected intellectual competence beyond age 60. While some memory loss was acknowledged, we found only four accounts of severe cognitive loss that might represent ADRD. The possibility of modest ADRD prevalence in ancient Greece and Rome is consistent with its low prevalence in the Tsimane of Bolivia. These contemporary Amerindians live under conditions of high mortality from frequent infections and minimal cardiovascular disease with physically demanding lives. Tsimane after age 60 had increased mild cognitive impairment; the few cases of dementia were not clinically consistent with AD.

Senescent cells accumulate with age and contribute meaningfully to chronic inflammation and degenerative aging. Destroying these cells produces rapid and sizable reversal of age-related diseases in mice, demonstrating that the presence of senescence cells acts to maintain a more dysfunctional, inflamed metabolism. This is well known by now, and numerous biotech companies in the first wave of development of senolytic treatments to selectively destroy senescent cells are in varying stages of preclinical and clinical development. Meanwhile, the off-label use of dasatinib and quercetin, a low-cost senolytic therapy that is neither developed nor promoted by any company, continues to look promising based on the slow progression of clinical trials.

Cellular senescence is implicated in ageing and associated with a broad spectrum of age-related diseases. Importantly, a cell can initiate the senescence program irrespective of the organism's age. Various stress signals, including those defined as ageing hallmarks and alterations leading to cancer development, oncogene activation, or loss of cancer-suppressive functions, can trigger cellular senescence. The primary outcome of these alterations is the activation of nuclear factor (NF)-κB, thereby inducing the senescence-associated secretory phenotype (SASP). Proinflammatory cytokines and chemokines, components of this phenotype, contribute to chronic systemic sterile inflammation, commonly referred to as inflammageing. This inflammation is linked to age-related diseases (ARDs), frailty, and increased mortality in older individuals.

Additionally, senescent cells (SCs) accumulate in multiple tissues with age and are believed to underlie the organism functional decline, as demonstrated by models. An escalating effort has been dedicated to identify senotherapeutics that selectively target SCs by inducing apoptosis; these drugs are termed senolytics. Concurrently, small molecules that suppress senescent phenotypes without causing cell death are known as senomorphics. Both natural and synthetic senotherapeutics, along with immunotherapies employing immune cell-mediated clearance of SCs, currently represent the most promising strategies to combat ageing and ARDs. Indeed, it is fascinating to observe that information regarding the immune reaction to SCs indicates that regulation by specific lymphocyte subsets, elevated in the oldest centenarians, plays a role in attaining extreme longevity.

Link: https://doi.org/10.3390/ijms25031792

Dysregulation of nutrient sensing is one of the hallmarks of aging, and the work here illustrates that this dysregulation has downstream consequences to stem cell function in at least intestinal tissues. That said, it seems unlikely that this disruption of nutrient sensing in later life, in part caused by increased levels of the mTORC1 complex, is close to the root causes of aging. One might expect rejuvenation therapies targeting forms of damage and dysfunction that are closer to the causes of aging to result in restoration of more youthful nutrient sensing.

The adult intestine is a regionalized organ, whose size and cellular composition are adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell-type composition remains unclear. Here, we show that intestinal nutrient adaptation involves region-specific control of cell size, cell number, and differentiation.

We uncovered that activation of mTOR complex 1 (mTORC1) increases ISC size in a region-specific manner. mTORC1 activity promotes Delta expression to direct cell fate toward the absorptive enteroblast lineage while inhibiting secretory enteroendocrine cell differentiation. In aged flies, the ISC mTORC1 signaling is deregulated, being constitutively high and unresponsive to diet, which can be mitigated through lifelong intermittent fasting. In conclusion, mTORC1 signaling contributes to the ISC fate decision, enabling regional control of intestinal cell differentiation in response to nutrition.

Link: https://doi.org/10.1126/sciadv.adi2671

Today's open access paper outlines results from an epidemiological study, and is a fairly standard examination of the relationship between being overweight and outcomes such as increased risk of age-related disease and mortality. Being a modern study, it uses waist circumference rather than body mass index, as the most problematic fat tissue held by overweight individuals is the visceral fat in the abdomen. Visceral fat tissue is metabolically active, generating chronic inflammation via a range of mechanisms that include mimicking the signaling of infected cells, generating more senescent cells, and an increased burden of cell debris that triggers an innate immune reaction. This chronic inflammation in turn accelerates all of the common pathologies of aging.

Despite all of the evidence for visceral fat to be a bad thing, the low weight tertile often performs more poorly than one might expect in this sort of epidemiological study. The current consensus on the reasons for this outcome is that the lowest weight tertile includes people who have serious chronic issues and an outsized risk of mortality and disease. That is why they do not put on weight like most of the rest of the population. In most epidemiological databases it is somewhere between hard to impossible to distinguish exactly why it is that someone is of normal to low normal weight and thus exclude the problematic portions of the study population.

Association of changes in waist circumference, waist-to-height ratio and weight-adjusted-waist index with multimorbidity among older Chinese adults: results from the Chinese longitudinal healthy longevity survey (CLHLS)

The present study focused on the association of changes in waist circumference (WC), waist-to-height ratio (WHtR), and weight-adjusted-waist index (WWI) with multimorbidity among older Chinese adults. Our results showed that rising changes in WC, WHtR, and WWI were associated with an increased risk of multimorbidity. Compared with participants in the persistently low group of WC, WHtR, those in the gain group and the persistently high group of WC, WHtR had significantly higher multimorbidity risk. Moreover, compared with the persistently low WWI group, the WWI loss group was correlated with a lower risk of multimorbidity.

The association between adiposity and multimorbidity has been extensively explored in epidemiological studies. Although studies have consistently demonstrated that obesity is positively associated with multimorbidity, the studies on the relationship between obesity indicators change and multimorbidity are limited and still controversial.

In this study, we first explored the association between WC, WHtR, and WWI change patterns and multimorbidity. WC and WHtR are considered to be important anthropometric indicators of abdominal obesity. Previous studies have suggested that WC and WHtR can reflect body fat percentage accurately and play an important role in predicting some chronic diseases, such as cardiovascular disease and metabolic syndrome. The pathway may explain that abdominal obesity significantly increased plasma triglycerides, low density lipoproteins, and very low density lipoproteins, which have been shown to increase the risk of adverse outcomes such as cardiovascular disease, diabetes, hypertension, and kidney diseases. In addition, people with abdominal obesity tend to have excess visceral fat, which can lead to high doses of adipokines from the portal vein to the liver and other body tissues, causing a variety of chronic diseases. Previous studies have highlighted that visceral adipose tissue produces large amounts of interleukin-6 (IL-6), which promotes the secretion of acute-phase proteins such as C-reactive protein (CRP), and thus the levels of IL-6 and CRP are significantly increased in individuals with abdominal obesity.

Therefore, WWI loss may reduce inflammation and thus the risk of multimorbidity, which could reasonably explain our results. Moreover, the persistently low WWI group included those who had always been underweight, and underweight older adults were prone to malnutrition, which is associated with some noninfectious chronic diseases. This may explain why the risk of multimorbidity was higher in the persistently low WWI group than in the WWI loss group.

It is now commonplace for patients to undergo first generation stem cell therapy where the transplanted cells (which may or may not actually be stem cells) are derived from fat tissue. These therapies clearly produce some degree of benefit, primarily suppression of inflammation. There is a high degree of variability of outcomes between patients and from clinic to clinic, however, even when clinicians are following the same protocol. This may be due to the degree of cellular senescence that emerges in transplanted cells, but this is still a topic under investigation. Regardless, various different approaches have been assessed in order to improve the ability of transplanted cells to produce benefits in patients. The research noted here is one example of many.

Adipose-derived stem cells (ADSCs) have been widely applied in translational and regenerative medicine. However, during aging, there is a recognized functional decline in ADSCs, which compromises their therapeutic effectiveness. Currently, the mechanisms of aging-induced stem cell dysfunction remain unclear. Hence, there is a need to elucidate these mechanisms and propose strategies for reversing this functional impairment.

In this study, we found that ADSCs isolated from old donors (O-ADSCs) presented inferior phenotypes and decreased miR-145-5p levels compared to those from young donors (Y-ADSCs). To interrogate the role of miR-145-5p in ADSCs, gain- and loss-of-function approaches were performed. The results indicated that miR-145-5p overexpression in O-ADSCs promoted cellular proliferation and migration, while reducing cell senescence. Further study demonstrated that miR-145-5p could regulate ADSCs function by targeting bone morphogenetic protein binding endothelial cell precursor-derived regulator (BMPER), which is a crucial modulator in angiogenesis. Moreover, in vivo experiments showed that miR-145-5p-overexpressing O-ADSCs accelerated wound healing by promoting wound re-epithelialization and angiogenesis.

Collectively, this study indicates that miR-145-5p works as a positive regulator for optimizing O-ADSCs function, and may be a novel therapeutic target for restoring aging-associated impairments in stem cell function.

Link: https://doi.org/10.1242/bio.060117

How much of the declining function characteristic of aging is a matter of accumulated damage versus maladaptive responses to that damage? Damage to tissues alters the balance of molecules secreted by cells in those tissues, thereby changing the signaling environment both locally and throughout the body, causing other cells and tissues to react. Some of those reactions are harmful. The chronic inflammation of aging is a prominent example, the immune system serving as a broadcast network enabling dysfunction in one location in the body to contribute to harmful consequences everywhere else.

Aging brings about a myriad of degenerative processes throughout the body. A decrease in cognitive abilities is one of the hallmark phenotypes of aging, underpinned by neuroinflammation and neurodegeneration occurring in the brain. This review focuses on the role of different immune receptors expressed in cells of the central and peripheral nervous systems.

We will discuss how immune receptors in the brain act as sentinels and effectors of the age-dependent shift in ligand composition. Within this 'old-age-ligand soup,' some immune receptors contribute directly to excessive synaptic weakening from within the neuronal compartment, while others amplify the damaging inflammatory environment in the brain. Ultimately, chronic inflammation sets up a positive feedback loop that increases the impact of immune ligand-receptor interactions in the brain, leading to permanent synaptic and neuronal loss.

Link: https://doi.org/10.1042/BSR20222267

At least when considering study populations as a whole rather than individuals on their own, grip strength remains a decent proxy measure for risk of mortality and age-related disease. Loss of muscle mass and strength occurs for everyone in later life, leading to the condition known as sarcopenia, and is sensitive to many of the important mechanisms of aging, such as chronic inflammation. Low grip strength is likely indicative of a higher burden of cell and tissue damage throughout the body, because the mechanisms that contribute to loss of strength, such as inflammation, also contribute to other declines, forms of damage, and loss of function.

As noted in today's open access paper, there is a growing interest in age-related changes in the relative sizes of microbial populations making up the gut microbiome. With age there is a loss of beneficial metabolite production and an increase in pro-inflammatory microbial activity. This is thought to provide a significant contribution to degenerative aging, an influence on long-term health that is likely as sizable as the effects of lifestyle choices related to diet and physical fitness. Thus one might expect to see, as here, correlations between the aging of the gut microbiome and loss of grip strength in later life.

Serum metabolome and gut microbiome alterations are associated with low handgrip strength in older adults

Handgrip strength (HGS), which represents global muscle strength, is a powerful indicator of disability and mortality in older adults; it is also used for the diagnosis of possible or probable sarcopenia and physical frailty. This study aimed to explore the metabolic mechanisms and potential biomarkers associated with declining HGS among older adults. We recruited 15 age- and environment-matched inpatients (age, 77-90 years) with low or normal HGS. Liquid chromatography-mass spectrometry (LC-MS) and 16S ribosomal DNA (rDNA) gene sequencing were performed to analyze the metabolome of serum and stool samples and the gut microbiome composition of stool samples. Spearman's correlation analysis was used to identify the potential serum and fecal metabolites associated with HGS.

We assessed the levels of serum and fecal metabolites belonging to the class of cinnamic acids and derivatives and reported that the levels of carboxylic acids and their derivatives decreased in the low-HGS group. Serum levels of microbial metabolites, including cinnamoylglycine, 4-methoxycinnamic acid, and (e)-3,4,5-trimethoxycinnamic acid, were positively correlated with HGS. We found that gut microbial α-diversity was significantly higher in the low-HGS group, whereas higher β-diversity was observed in the normal group. The relative abundances of the genera Parabacteroides and Intestinibacter increased significantly in the low-HGS group and were negatively correlated with the serum levels of cinnamoylglycine. The identified metabolites whose levels were markedly altered, and intestinal flora associated with these metabolites suggest the potential metabolic underpinnings for HGS and provide a basis for the further identification of biomarkers of muscle strength decline in older adults.

Studies over the past decade have made it clear that waist circumference is a better measure of the degree of harm resulting from excess fat tissue than body mass index. It is the visceral fat tissue packed around abdominal organs that is the harmful form of fat, when present in excessive amounts. It is metabolically active, promoting chronic inflammation and a greater burden of senescent cells. Thus any measure of fat in the abdomen is likely going to have a better correlation with age-related disease and mortality than a more global measure of fat throughout the body.

Obesity in midlife is a modifiable risk factor for dementia; however, in later life, a higher body mass index (BMI) has a protective effect. This discordance in findings might be due to the reverse causation of weight loss beginning approximately 10 years before the onset of dementia. It is also possible that BMI does not adequately reflect nutritional status (degree of obesity or weight loss) in later life. This discrepancy arises because older adults usually experience changes in body composition in which fat mass increases and fat-free mass decreases with age, although the change in BMI is small.

In this context, recent studies have measured abdominal adiposity using waist circumference (WC) and waist-hip ratio, but not BMI, to assess nutritional status. Higher WC and waist-hip ratio are associated with the development of dementia and brain structural changes, such as hippocampal atrophy and white matter hyperintensity, in later life. Based on the results of these studies, the accumulation of abdominal adiposity may have an adverse effect on brain health in later life.

This study investigated the association between abdominal adiposity at baseline and change in cognitive function in community-dwelling older adults using longitudinal data collected separately for men and women over 10 years. Cognitive function was evaluated biennially using the Mini-Mental State Examination (MMSE) over 10 years. Waist circumference (WC) was measured at the naval level, and subcutaneous fat area (SFA) and visceral fat area (VFA) were assessed using baseline computed tomography scans.

This study included 873 older adults. In men, the groups with the highest levels of WC, SFA, and VFA exhibited a greater decline in MMSE score than the groups with the lowest levels, with standardized coefficient β: WC, -0.12; SFA, -0.13; VFA, -0.11. In women, the group with the highest level of WC and SFA showed a greater decline in MMSE score than the group with the lowest level, with β: WC, -0.12; SFA, -0.18), but VFA was not associated with cognitive decline.

Link: https://doi.org/10.1016/j.jnha.2024.100175

Some fraction of the chronic inflammation of aging emerges because mitochondrial stress and dysfunction causes ejection of mitochondrial DNA fragments into the cell cytoplasm, where these fragments trigger the cGAS-STING pathway and consequent inflammatory signaling. Cells have evolved to be vigilant to misplaced DNA in large part because it is a marker of viral or bacterial infection. Obtaining a better understanding of the mechanisms involved in this process may identify points of intervention, ways to selectively suppress either the exposure of mitochondrial DNA in the cytoplasm or the reaction to that DNA when it is exposed.

While the innate immune response is the first line of defense against viruses, it can also respond to molecules the body makes that resemble pathogens - including misplaced mitochondrial DNA (mtDNA). This response can lead to chronic inflammation and contribute to human diseases and aging. Scientists have been working to uncover how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathways did not apply to all mtDNA stress conditions. Researchers turned to sophisticated imaging techniques to gather clues as to where and when things were going awry in those mitochondria.

The team discovered a process beginning with a malfunction in mtDNA replication that caused mtDNA-containing protein masses called nucleoids to pile up inside of mitochondria. Noticing this malfunction, the cell then begins to remove the replication-halting nucleoids by transporting them to endosomes, a collection of organelles that sort and send cellular material for permanent removal. The endosome gets overloaded with these nucleoids, springs a leak, and mtDNA is suddenly loose in the cell. The cell flags that mtDNA as foreign DNA - the same way it flags a virus's DNA - and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.

The researchers hope to map out more of this complicated mtDNA-disposal and immune-activation pathway, including what biological circumstances - like mtDNA replication dysfunction and viral infection - are required to initiate the pathway and what downstream effects there may be on human health. They also see an opportunity for therapeutic innovation using this pathway, which represents a new cellular target to reduce inflammation.

Link: https://www.eurekalert.org/news-releases/1033508

The innate immune system is involved in tissue maintenance and regeneration. That includes populations of monocytes, circulating innate immune cells in the bloodstream that enter damaged tissue to become macrophages. Monocytes are somewhat easier to catalog and study than is the case for macrophages. The former can be found in a blood sample, while the latter require a tissue sample. Researchers tend to follow the incentives attending the cost and availability of data, and thus we have examples like today's open access paper, in which the authors focus on circulating monocytes in the context of bone fracture.

You might read this paper as a companion piece to a recent investigation of the bad behavior of macrophages in aged bone, and their tendency to do more harm than good following injury. How much of this altered macrophage behavior can be traced back to differences in circulating monocyte populations? No doubt at least some researchers will be looking into this question in the years ahead. Manipulation of innate immune cell state is a growing area of interest for the research community, and while not straightforward, there is the promise of being able to better control tissue maintenance, regeneration, and inflammation.

Monocyte alteration in elderly hip fracture healing: monocyte promising role in bone regeneration

One of the body systems profoundly affected by aging is the skeletal system, giving rise to conditions such as osteoporosis and osteoarthritis that become increasingly prevalent with age. Additionally, there is a notable upswing in the incidence of bone fractures, which is associated with higher rates of morbidity and mortality. Among these fractures, hip fractures (HF) stand out as particularly concerning due to their severe consequences. HF not only leads to chronic pain and disability but also entails a high morbidity risk, an increased susceptibility to major depression, and a loss of autonomy, and often necessitates institutionalization for individuals who were previously independent.

Peripheral blood monocytes, a heterogeneous population comprising approximately 10% of peripheral leukocytes in humans, play a pivotal role in both innate and adaptive immunity. They function as phagocytic cells, eliminating pathogens, and also produce cytokines. Understanding the roles and mechanisms of macrophages, which monocytes can differentiate into, in the context of fractures, may provide valuable insights into predicting the timing of surgery for HF patients and mitigating the immunosuppressive effects that contribute to mortality.

A notable change in older adults is the increased expression of activation, adhesion, and migration markers in circulating monocytes. However, there is a decrease in the expression of co-inhibitory molecules. Recently, research evidence has shown that the migration of specific monocyte subsets to the site of hip fracture plays a crucial role in bone resorption and remodeling, especially concerning age-related factors. In this review, we summarize the current knowledge about uniqueness characteristics of monocytes, and their potential regulation and moderation to enhance the healing process of hip fractures. This breakthrough could significantly contribute to the comprehension of aging process at a fundamental aging mechanism through this initiative would represent a crucial stride for diagnosing and treating age related hip fracture.

Epigenetic clocks are produced from data on the status of DNA methylation at CpG sites in the genome at various ages via machine learning processes. Thus it is unclear as to what the clocks actually measure. There is no catalog to state how and why each CpG site on the genome is or is not methylated at any given time. There is little to no understanding of the mechanistic links between specific epigenetic marks such as DNA methylation and specific mechanisms and states of aging. In that context, the work here is interesting, demonstrating that stochastic epigenetic dysregulation with age, known as epigenetic drift, contributes to clocks, but isn't the whole story.

Changes in DNA methylation with age are observed across the tree of life. The stereotypical nature of these changes can be modeled to produce epigenetic clocks capable of predicting chronological age with unprecedented accuracy. Despite the predictive ability of epigenetic clocks and their utility as biomarkers in clinical applications, the underlying processes that produce clock signals are not fully resolved, which limits their interpretability.

Here, we develop a computational approach to spatially resolve the within read variability or "disorder" in DNA methylation patterns and test if age-associated changes in DNA methylation disorder underlie signals comprising epigenetic clocks. We find that epigenetic clock loci are enriched in regions that both accumulate and lose disorder with age, suggesting a link between DNA methylation disorder and epigenetic clocks. We then develop epigenetic clocks that are based on regional disorder of DNA methylation patterns and compare their performance to other epigenetic clocks by investigating the influences of development, lifespan interventions, and cellular dedifferentiation.

We identify common responses as well as critical differences between canonical epigenetic clocks and those based on regional disorder, demonstrating a fundamental decoupling of epigenetic aging processes. Collectively, we identify key linkages between epigenetic disorder and epigenetic clocks and demonstrate the multifaceted nature of epigenetic aging in which stochastic processes occurring at non-random loci produce predictable outcomes.

Link: https://doi.org/10.18632/aging.205503

Allostatic load is the concept of wear and tear on the body that emerges from stresses via overactivation of the neuroendocrine system. Causative stresses can range from starvation to psychological stress to a high burden of age-related dysfunction. At some point reactions to stress that are compensatory tip over into being themselves damaging. Thus one could expect allostatic load to correlate with degenerative aging and risk of mortality to at least some degree. In practice, however, there is little agreement on how to measure allostatic load, particularly in human patients, which makes it hard to compare results from study to study, and hard to form a unified body of work from the research on the topic.

Allostatic load (AL) refers to the activation of physiological regulatory systems in response to chronic stress and the long-term effects on the body and brain. AL reflects cumulative, multisystem physiological dysregulation, which is the result of repeated cycles over the lifespan in response to stressful life evens events. A literature review of AL and health reported that older and disadvantaged groups exhibited a higher risk of high AL. The primary mediators of AL include stress hormones and cytokines that influence the secondary outcomes of systematic dysregulation of metabolic, cardiovascular, and second-order inflammatory biomarkers over time.

Importantly, adults aged over 40 years old had a more than 2-fold higher risk of high AL than adults aged 18-29 years old. The effect of increased AL varies according to age, as well as multiple health-related and clinical factors. The aims of this study were to explore 1) the association of age and depressive symptoms with allostatic load and 2) whether socioeconomic (e.g., birth-assigned sex, educational level, marital status) and/or lifestyle factors (e.g., current smoking, high alcohol consumption, no physical exercise) are associated with high AL.

Thirteen biomarkers were used to construct AL. High AL was defined as scoring highly in ≥4 items. AL scores of 4 and above were exceeded in the age group of 45-54 years in men and 65-74 years in women. Age was the strongest predictor for belonging to the high AL score group. In addition, elevated depressive symptoms (BDI-6 ≥ 4), male sex, not engaging in physical exercise, high alcohol use, and a low level of education were associated with an increased likelihood of belonging to the high AL group.

Link: https://doi.org/10.1016/j.jad.2024.01.189

Rapamycin and some of the later rapalog derivatives such as everolimus, all of which function via inhibition of mTOR, are arguably the best of the present crop of geroprotective drugs capable of modestly slowing aging and extending life in animal studies. The effects of rapamycin in mice are robust and repeatable, though never as large as we'd all like them to be. Like many of the other interventions that modestly slow aging in animal models these small molecule drugs mimic some of the effects of calorie restriction, and likely produce benefits largely through increased efficiency of the cell maintenance processes of autophagy. Better recycling of damaged and unwanted proteins and structures leads to better cell function, fewer senescent cells, and better tissue function.

From what is known of the differences between mice and humans in the use of calorie restriction as an intervention, the effect on life span of any strategy based on upregulation of autophagy via pathways relevant to calorie restriction is likely smaller in humans than it is in mice. In the case of rapamycin, there is human data for short-term and mid-term effects on health, but nothing useful for life span. Rapamycin has been widely used for decades in various contexts, and a fair-sized population of self-experimenters is presently using rapamycin at the established anti-aging dosage, somewhere in the vicinity of 5mg taken orally once per week. One thing that is clear from the human data is that rapamycin use at this dose appears comparatively safe.

Targeting ageing with rapamycin and its derivatives in humans: a systematic review

Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18,400 unique articles, resulting in 19 included studies.

Rapamycin and its derivatives improved the immune, cardiovascular, and integumentary systems in healthy individuals or individuals with ageing-related diseases. Overall, these drugs had no significant effects on the endocrine, muscular, or neurological systems. The effects of rapamycin or its derivatives on the respiratory, digestive, renal, and reproductive systems were not assessed. There was no clear relationship between the dose of rapamycin or its derivatives and the effects of these drugs on different physiological systems. No serious adverse events were attributed to the interventions.

Although studies have reported that rapamycin and its derivatives can enhance learning and memory, and reduce neurodegeneration in animal models, these effects were not observed in the human studies assessed in this systematic review. Moreover, the reported effects on ageing-related macular changes were inconsistent. For instance, rapamycin reduced the need for anti-VEGF usage but also led to the loss of visual acuity in individuals with geographic atrophy in age-related macular degeneration. In addition, in preclinical studies, pharmacological mTOR inhibition reduced age-related cardiac inflammation, fibrosis, hypertrophy, and systolic dysfunction. Although improvements in the cardiac index and reductions in both pulmonary vascular resistance and pulmonary arterial pressure have been observed following intervention with everolimus, the effects of rapamycin and its derivatives on cardiovascular parameters in humans should be assessed more comprehensively in future studies.

As individuals age, their glucose tolerance declines. Overactivation of the mTOR pathway leads to the activation of S6K-1 and phosphorylated IRS-1, impairing the stimulation of PI3K by insulin and, subsequently, lowering insulin resistance in human muscle. The effects of rapamycin on glucose metabolism differed by study setting. Although rapamycin treatment increased glucose turnover under conditions of induced peripheral hyperinsulinaemia, it did not affect glucose turnover when there was low peripheral insulin, and did not affect post-exercise insulin concentrations, or post-amino acid infusion fasting insulin, C-peptide, glucose, or glucagon concentrations.

mTOR is hypothesised to be a crucial regulator responsible for maintaining skeletal muscle mass. Although animal studies investigating mTOR inhibition by rapamycin and its derivatives on the muscular system have reported inconsistent results, the human studies we assessed reported no significant effects. However, in these studies, rapamycin was administered in single doses. Further research with different dosing regimens might be necessary to better understand the potential effects of rapamycin and its derivatives on the muscular system.

Topical rapamycin significantly reduced the expression of markers of skin ageing. However, the effects of systemically administered rapamycin or its derivatives on the skin were not investigated and, therefore, require further research.

As individuals age, their capacity to mount a robust immune response diminishes, rendering them more vulnerable to infections and poor response to vaccinations. The mTOR pathway is a crucial signalling pathway within the immune system, controlling the activation, proliferation, differentiation, and function of immune cells. Although rapamycin is known to be immunosuppressive, there are several mechanisms that might explain the immunostimulatory effect of rapamycin in vitro and in animal studies, such as the improvement of immune memory, alteration of CD8+ cell response, and promotion of regulatory T-cell survival and function. In the studies analysed in this review, rapamycin and its derivatives improved immune function mainly by altering adaptive immunity.

There was no clear relationship between the dose of rapamycin or its derivatives and the efficacy of these drugs in ameliorating ageing-related outcomes in the assessed studies. This finding suggests that even though the pharmacokinetics of rapamycin are well known, pharmacodynamic studies that focus on target (ie, mTOR) engagement and the effects of rapamycin on ageing-related biomarkers are needed to establish an adequate dosing regimen for geroprotection.

In comparison to presently expanding studies of the gut microbiome, much less effort is directed towards the skin microbiome in the context of aging. Given the existence of the sizeable and vocal cosmetics industry, I'm sure that will change in the years ahead, however. For now, research into mechanisms by which the skin microbiome might change with age and in turn affect the aging of skin remains lagging somewhat behind the equivalent programs focused on intestinal microbial populations and their effects on the aging body and brain.

The interplay between microbes and the skin barrier holds pivotal significance in skin health and aging. The skin and gut, both of which are critical immune and neuroendocrine system, harbor microbes that are kept in balance. Microbial shifts are seen with aging and may accelerate age-related skin changes. This comprehensive review investigates the intricate connection between microbe dynamics, skin barrier, and the aging process. The gut microbe plays essential roles in the human body, safeguarding the host, modulating metabolism, and shaping immunity.

Aging can perturb the gut microbiome which in turn accentuates inflammaging by further promoting senescent cell accumulation and compromising the host's immune response. Skin microbiota diligently upholds the epidermal barrier, adeptly fending off pathogens. The aging skin encompasses alterations in the stratum corneum structure and lipid content, which negatively impact the skin's barrier function with decreased moisture retention and increased vulnerability to infection. Efficacious restoration of the skin barrier and dysbiosis with strategic integration of acidic cleansers, emollients with optimal lipid composition, antioxidants, and judicious photoprotection may be a proactive approach to aging. Furthermore, modulation of the gut-skin axis through probiotics, prebiotics, and postbiotics emerges as a promising avenue to enhance skin health as studies have substantiated their efficacy in enhancing hydration, reducing wrinkles, and fortifying barrier integrity.

In summary, the intricate interplay between microbes and skin barrier function is intrinsically woven into the tapestry of aging. Sound understanding of these interactions, coupled with strategic interventions aimed at recalibrating the microbiota and barrier equilibrium, holds the potential to ameliorate skin aging. Further in-depth studies are necessary to better understand skin-aging and develop targeted strategies for successful aging.

Link: https://doi.org/10.3389/fphys.2024.1322205

Here researchers discuss the influence of the hallmarks of aging paper, and its later expansions, on the field of aging research. You might read it at the same time as an earlier critique, and a related argument for greater consideration of cause and consequence. The hallmarks were never intended to be a list of causative mechanisms of aging, a list of mechanisms to target for intervention, but some of the hallmarks are indeed important causative mechanisms, and thus perhaps too many people take the whole list that way. The true list of proposed causes and points of intervention is the original Strategies for Engineered Negligible Senescence (SENS) proposal, predating the hallmarks of aging by a decade.

The Hallmarks of Aging arose as an answer to the great amount of information generated by aging research, with the aim of creating a conceptual framework to integrate and organize the existing knowledge. The objective of the present review has been to determine the impact of the Hallmarks and address if the purpose that gave them rise was achieved. For that aim, we reviewed the literature that cited any of the two versions of the Hallmarks. The conclusion was that the first version (with the second one also following the same trend) accomplished the goal, as it influenced a vast variety of fields ranging from the different areas of aging research to other related fields. Furthermore, it also inspired other authors and served as a model for the organization of knowledge, giving rise to a wide variety of "Hallmarks" in other subjects.

Nevertheless, this impact was not unidirectional, since the research promoted by the first version of the Hallmarks generated a great deal of knowledge that gave rise to the updates included in the second version. This updated version included three new hallmarks and, in spite of its recent publication, it is being highly cited and has already influenced some studies and served as a knowledge-structuring model. Therefore, it can be concluded that the usefulness of The Hallmarks of Aging in aging-related research seems undeniable.

However, as any approximation it has its limitations and it should be carefully revised, considering the latest advances, to determine whether all the hallmarks are still valid and if it is necessary to include new ones. In this sense, this review has analyzed the possible emerging hallmarks that were not included in the second version and the ones that were included but as components of other hallmarks. Assuming that a conceptual framework must be as schematic and organized as possible and the still limited evidence supporting some of these candidate hallmarks, we conclude that further investigations are needed to assess if any of these proposed hallmarks should be included in the next version. Even though the current Hallmarks of Aging provide a valid scaffold for aging research, there is no doubt that, as knowledge advances, updated versions of the Hallmarks will become necessary.

Link: https://doi.org/10.3389/fragi.2024.1334261

An incrementally greater understanding of the complex mechanisms driving any given age-related dysfunction will usually offer new approaches to intervention. Even if those approaches do not address root causes, sometimes preventing only the proximate causes can still meaningfully improve outcomes. In today's open access paper, researchers outline specific age-related changes in macrophage behavior that lead to greater cellular senescence in the stem cell and progenitor cell populations important to repair of damaged bone. That greater burden of cellular senescence impairs regeneration following bone injury.

This is one of many examples one might choose to use in order to illustrate the complexity of the relationship between the immune system and other cells in tissues, particularly in the context of regeneration. Innate immune cells such as macrophages clearly play an important role in tissue maintenance and regeneration from injury, as do transient senescent cells. Equally clearly, these cell populations undergo significant changes with age, including greater inflammatory behavior and too many lingering senescent cells. Absent a very specific understanding of the way in which these changes negatively impact other cell populations, it is hard to proceed towards selective interventions, however. One must fall back to senolytic therapies to clear the senescent cells that are known to be a problem without a full understanding of how those cells became senescent.

Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing

Osteoporosis is characterized by low bone mass and destroyed microarchitecture, resulting in an increased risk of fracture. Additionally, decreased bone regenerative potential and a high risk of impaired or incomplete fracture healing in elderly individuals contribute to long-term disability or even death. However, the etiology of age-related impaired skeletal regenerative capacity remains incompletely understood.

Aged-related skeletal deterioration and impaired fracture healing are related to the accumulation of senescent cells, which are characterized by permanent cell cycle arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). Our previous study found that senescent immune cells accumulated in the bone marrow and secreted grancalcin (GCA), which suppressed bone turnover and promoted marrow fat accumulation. Thus, accumulated senescent cells in the bone microenvironment play a significant role in skeletal aging, and eliminating senescent cells and/or blunting their SASP factors can prevent or delay age-related bone loss. Recent studies also suggested that the accumulation of senescent cells impaired fracture healing, and removing senescent cells by genetic and pharmacological approaches in aged mice improved fracture repair. However, the effects and underlying mechanisms of senescent cells in fracture healing during aging remain elusive.

In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers skeletal stem cell and progenitor cell (SSPC) senescence and impairs fracture healing. Local injection of human recombinant GCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for incomplete fracture healing in elderly individuals.

In this paper, the authors discuss the overlap between oxidative stress and growing numbers of senescent cells in the brain. Both are thought to contribute to neurodegenerative conditions such as Alzheimer's disease. The aging of the brain is complex, a web of interacting processes, causes, and consequences. It has proven to be difficult to determine which processes are more or less important; the only efficient way forward is to come up with interventions that remove just one contributing factor with minimal side-effects. That is now possible for senescent cells, and clinical trials are underway, but manipulation of oxidative stress without changing other factors is a much more challenging prospect.

The redox process and cellular senescence are involved in a range of essential physiological functions. However, they are also implicated in pathological processes underlying age-related neurodegenerative disorders, including Alzheimer's disease (AD). Elevated levels of reactive oxygen species (ROS) are generated as a result of abnormal accumulation of beta-amyloid peptide (Aβ), tau protein, and heme dyshomeostasis and is further aggravated by mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Excessive ROS damages vital cellular components such as proteins, DNA, and lipids. Such damage eventually leads to impaired neuronal function and cell death.

Heightened oxidative stress can also induce cellular senescence via activation of the senescence-associated secretory phenotype to further exacerbate inflammation and tissue dysfunction. In this review, we focus on how changes in the redox system and cellular senescence contribute to AD and how they are affected by perturbations in heme metabolism and mitochondrial function. While potential therapeutic strategies targeting such changes have received some attention, more research is necessary to bring them into clinical application.

Link: https://doi.org/10.1016/j.redox.2024.103048

Senescent cells accumulate with age, and this accumulation drives a sizable fraction of the dysfunction of degenerative aging. While never present in very large numbers, these cells energetically secrete signal molecules that provoke inflammation and tissue remodeling. As noted here, a major theme in the development of senotherapeutic drugs to either selectively destroy senescent cells or broadly suppress the disruptive signaling of senescent cells is the need for greater understanding of the diversity of cellular senescence. Different tissues, different cell types, different origins of the senescent state may all be meaningfully different in their responses to drugs targeting one or another of the mechanisms identified to be important in cellular senescence. While early senolytic drugs are quite impressive in the benefits they produce in aged mice, later therapies produced in an environment of greater understanding will be better.

During the first senotherapeutics conference organized by the Phaedon Institute at the Buck Institute for Research on Aging, experts on the molecular and cellular mechanisms of aging, pathogenesis of age-related diseases, and drug discovery and development convened to delve into ideas on the past, present, and future of targeting senescent cells. A focal point of discussion revolved around the heterogeneity of cellular senescence, and its profound implications for the development of treatments. Presenters highlighted the diverse profiles of senescent cells, emphasizing differences in gene expression, secretory patterns, and functional roles, in addition to the importance of the tissue microenvironment.

Senescent cells represent a potential target for geroprotection and reduction of multimorbidity, but owing to current regulations, clinicians and pharmaceutical companies are focusing on the use of senotherapeutics for specific and selective age-related diseases. A Phase 2B trial sponsored by Unity Biotechnology is currently ongoing for the treatment of Diabetic Macular Edema (DME) using the senolytic agent UBX1325, which inhibits Bcl-XL. The Translational Geroscience Network runs a number of Phase 1 and Phase 2 trials using senolytic compounds, such as Dasatinib, Quercetin, and Fisetin, for the treatment of sepsis, chronic kidney disease, lung fibrosis, and Alzheimer's disease. Additionally, many other pathological conditions have been discussed as potential indications for the use of therapeutic compounds. For example, efforts are currently being made to selectively target senescent cell subtypes in pre-clinical models of skin and muscle dysfunctions with novel senolytic small molecules in development at Rubedo Life Sciences and Boehringer-Ingelheim, respectively.

While these represent pioneering studies and the opportunity to demonstrate the unequivocal pathological role of certain senescence subsets, challenges remain in the path to harnessing the therapeutic potential of targeting cellular senescence. Participants emphasized the need for a more comprehensive understanding of the dynamic nature of senescent cells, their role and localization in various tissues and tissue areas, and the need for more accurate and sensitive biomarkers. This discussion highlighted the importance of multi-laboratory and multi-center efforts in adapting the newest technologies with single-cell resolution for the identification and specification of senescent cells in vivo. These studies can offer novel targets for interventions and novel markers for a standardized evaluation of the efficacy of anti-senescence approaches in humans. Overall, the pleiotropic diversity and heterogeneity of cellular senescence invites the development of diverse strategies and modalities to target subsets of senescent cells according to their physiopathological roles. The ongoing effort in academic and industrial laboratories to develop different senotherapeutics is strategic to enable advancement in the clinic of multiple novel therapeutic opportunities, possibly in parallel.

Link: https://doi.org/10.1038/s41514-024-00139-3

Frailty is an inevitability for everyone on some timescale, given the present state of medical technology. It is not, however, an inevitability for early old age. It can be postponed for decades. Further, if someone becomes frail in earlier old age, that frailty may be reversible given sufficient effort put into treatment and lifestyle changes, particularly those involving resistance exercise. A perhaps surprisingly large fraction of the progressive loss of muscle mass and strength with age is a matter of lack of use, a sedentary lifestyle, and other factors that provoke metabolic dysfunction and inflammation. Some fraction of the chronic inflammation of aging can be reduced or evaded.

The study population in today's open access paper is notable for the sizable reduction in risk of mortality and cardiovascular disease exhibited in the cohort that managed to reverse their slide into pre-frailty or outright frailty. For a moment let us set aside the means by which these patients achieved this goal, and why they succeeded where others failed. Just looking at the data, this should be taken as one more compelling reason to fund the development of therapies that can effectively reverse frailty for everyone, not just the fortunate few, by meaningfully targeting the driving factors of failing muscle tissue and and overly-inflammatory immune system.

Association of changes in frailty status with the risk of all-cause mortality and cardiovascular death in older people: results from the Chinese Longitudinal Healthy Longevity Survey (CLHLS)

Few studies have investigated the association between changes in frailty status and all-cause mortality, inconsistent results were reported. What's more, studies that evaluated the effect of changes of frailty on cardiovascular death in older population are scanty. Therefore, the present study aims to investigate the association of such changes with the risk of all-cause mortality and cardiovascular death in older people, using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS).

A total of 2,805 older participants from two consecutive waves (i.e. 2011 and 2014) of the CLHLS were included for analysis. Based on the changes in frailty status from wave 2011 to wave 2014, participants were categorized into 4 subgroups, including sustained pre/frailty, robustness to pre/frailty, pre/frailty to robustness, and sustained robustness. Study outcomes were all-cause mortality and cardiovascular death, and Cox regression analysis examined the association of changes in frailty status with outcomes.

From wave 2011 to wave 2014, 33.2% of the participants had frailty transitions. From wave 2014 to wave 2018, there were 952 all-cause mortalities and 170 cardiovascular deaths during a follow-up of 9530.1 person-years, and Kaplan-Meier analysis demonstrated that cumulative incidences of the two outcomes were significantly lower in more robust participants. Compared with the subgroup of sustained pre/frailty, the fully adjusted hazard ratios (HRs) of all-cause mortality were 0.61, in the subgroup of robustness to pre/frailty, 0.51 in the subgroup of pre/frailty to robustness, and 0.41 in the subgroup of sustained robustness, respectively. The fully adjusted HRs of cardiovascular death were 0.79 in the subgroup of robustness to pre/frailty, 0.45 in the subgroup of pre/frailty to robustness and 0.51 in the subgroup of sustained robustness when comparing to the subgroup of sustained pre/frailty, respectively. Stratified analysis and extensive sensitivity analyses revealed similar results.

In conclusion, frailty is a dynamic process, and improved frailty and remaining robust are significantly associated with lower risk of all-cause mortality and cardiovascular death in older people.

Should we expect an approach focused on repair of synapses in neurodegenerative conditions like Alzheimer's disease, while leaving the causative mechanisms of the condition operating intact, to have a large effect on patient outcomes? Given what is known of the underlying mechanisms of protein aggregation, neuroinflammation, and other problems that ultimately kill neurons, not just damage them, it seems possible that synaptic repair might do well in the early stages of cognitive impairment, but later do little to help as the condition progresses. Regardless, it is interesting to consider to degree to which neural function could in principle be maintained in the face of damaging mechanisms, without actually addressing those mechanisms.

While newly approved drugs for Alzheimer's show some promise for slowing the memory-robbing disease, the current treatments fall far short of being effective at regaining memory. Since most current research on potential treatments for Alzheimer's focuses on reducing the toxic proteins, such as tau and amyloid beta, that accumulate in the brain as the disease progresses, researchers veered away from this route to explore an alternative. The work hinges on a protein called KIBRA, named because it is found in the kidney and the brain. In the brain, it is primarily localized at the synapses, which are the connections between neurons that allow memories to be formed and recalled. Research has shown that KIBRA is required for synapses to form memories, and the team has found that brains with Alzheimer's disease are deficient in KIBRA.

The team first measured the levels of KIBRA in the cerebrospinal fluid of humans. They found that higher levels of KIBRA in the cerebrospinal fluid, but lower levels in the brain, corresponded to the severity of dementia. To figure out how KIBRA affects synapses, the team created a shortened functional version of the KIBRA protein. In laboratory mice that have a condition mimicking human Alzheimer's disease, they found that this protein can reverse the memory impairment associated with this type of dementia. They found that KIBRA rescues mechanisms that promote the resilience of synapses. "Interestingly, KIBRA restored synaptic function and memory in mice, despite not fixing the problem of toxic tau protein accumulation. Our work supports the possibility that KIBRA could be used as a therapy to improve memory after the onset of memory loss, even though the toxic protein that caused the damage remains."

Link: https://www.buckinstitute.org/news/buck-scientists-discover-a-potential-way-to-repair-synapses-damaged-in-alzheimers-disease/

Cancerous tissue co-opts the immune system, suppressing its ability to destroy cancerous cells, and even gaining the assistance of immune cells in encouraging the growth of a tumor. There are many different mechanisms by which this happens, varied by immune cell type and form of cancer, comparatively few of which are well mapped and well understood. The active and well-funded cancer research community continues to explore the potential to interfere in these harmful interactions between cancer and immune system. The approach noted here is one of many, and typical of this sort of research program in that it targets a specific subset of immune cells.

Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning, and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells.

We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.

Link: https://doi.org/10.1038/s41467-024-44789-z

The authors of the Death of Death are regulars on the conference circuit for aging research, the longevity industry, and patient advocacy for the treatment of aging as a medical condition. The book was originally in Spanish, and has finally been translated into English. It is a popular science overview of progress towards technologies that will first slow aging, then enable the control of aging, and eventually, at some point, produce large gains in healthy human life span, postponing death by aging essentially indefinitely. The book and its authors also unapologetically and straightforwardly stand in opposition to the horrors of having to decline, become sick, and die, when one would rather not. I think that we need a lot more of that sort of sentiment in the world. Less acceptance, and more raging against the dying of the light, is the path that leads to the medical technologies of rejuvenation.

The Death of Death

It is commonly thought that death is the natural consequence of life. In time, everything decays. Sooner or later, the old must make way for the new. In that case, won't death always be with us?

Actually, biology provides many indications that there is no necessity for living creatures to age and die. The more that we study biology, the more we can appreciate that life has an innate potential to keep on living. That's what we learn from various unicellular organisms, and also from the sad example of cancer cells. It is also what we learn from organisms that have negligible senescence: although these animals become chronologically older, they don't become biologically older, meaning that their likelihood of dying in the next twelve months remains constant from maturity onward. In other words, nature already possesses intrinsic mechanisms for rejuvenation, damage repair, and indefinite life spans. It's the task of rejuveneers - the engineers of methods of rejuvenation - to understand, improve, and augment these mechanisms, so that humans, likewise, can experience indefinite lifespans.

Different organisms have evolved to have different lifespans. Indeed, some creatures have evolved to have negligible senescence. But aren't these lifespans fixed?

On the contrary, over recent decades, a great deal of evidence has emerged about the plastic nature of lifespan. Numerous experiments have increased the typical lifespan - and typical healthspan - of creatures such as worms, fruit flies, mice, rats, fish, and more. Among other things, we now know about large numbers of genes that control parts of the aging process, about the role of the enzyme telomerase to allow cells to keep on dividing, about a range of "pillars" of aging, about the problems caused by the accumulation of different types of damage within and between cells, and, crucially, about interventions that have the potential to comprehensively address each of these types of damage - by removing, renewing, repairing, or reprogramming aspects of our biological makeup.

For more than a hundred years, scientists have been talking about extending human lifespan. So far, progress is slow. Since the year 1997, no one has reached an age higher than 119 years. Transferring potential treatments from mice to humans frequently hits problems. Isn't a significant extension of human lifespans something for the far future, rather than an imminent possibility?

We need to be aware of the common pathway for major technological breakthroughs. The hopes of visionaries often proceed slowly and disappointingly before reaching tipping points and then leaping forward. Prior to the tipping points, a general scepticism often prevailed, before being forgotten. Examples can be found in the fields of transport, communications, energy, and computation. The solution of aging will move along the same trajectory from "impossible" to "indispensable". In practical terms, what will accelerate progress is the parallel emergence of what will likely become the world's largest industry - the anti-aging industry - and the world's largest activist community - the anti-aging community. Until recently, many scientists were shy to speak of their ideas for solving aging, but they are increasingly finding their voice. A combination of science, business, finance, activism, and governments will drive the realisation of a new paradigm: that aging can, and should, be treated and cured.

Even though these new treatments may arrive in a few decades, that will be too late for many people, who may succumb to disease beforehand. What advice is available for them?

The best advice - "Plan A" - is to take steps to remain in good health long enough that it will be possible to take advantage of rejuvenation treatments when they become available. In other words, remain alive long enough to be able to live forever. However, there's a "Plan B" option that people should consider as well: low temperature cryopreservation at the time that they are declared legally dead. Arguments against cryonics mirror those against the reversal of aging: supposedly, it can't be done, and even if it could be done, it shouldn't be done. In both cases, the arguments are mistaken. There's plenty of evidence that cryonics can provide an "ambulance to the future" so that people who have the misfortune to die "at the wrong time" can be given another chance to reunite with family and friends.

There is ample evidence to show that air pollution correlates with increased mortality, and a number of natural experiments have allowed researchers to compare populations with similar socioeconomic status and different levels of air pollution, in order to demonstrate that effects do not result from wealth disparities. The consensus on why air pollution correlates with mortality is that interaction between particulates and lung tissue provokes greater systemic inflammatory signaling. That raised chronic inflammation accelerates the progression of all of the common fatal age-related conditions.

We aimed to report real-world longitudinal ambient air pollutants levels compared to WHO Air Quality Guidelines (AQG) and analyze multiple air pollutants' joint effect on longevity, and the modification and confounding from the climate and urbanization with a focus on the oldest-old. This study included 13,207 old participants with 73.3% aged 80 and beyond, followed up from 2008 to 2018 in 23 Chinese provinces. We used the Cox-proportional hazards model and quantile-based g-computation model to measure separate and joint effects of the multiple pollutants. We adjusted for climate and area economic factors based on a directed acyclic graph.

In 2018, no participants met the WHO AQG for PM2.5 and O3, and about one-third met the AQG for NO2. The hazard ratio (HR) for mortality was 1.07 per decile increase in all three pollutants, with PM2.5 being the dominant contributor according to the quantile-based g-computation model. In the three-pollutant model, the HRs for PM2.5 and NO2 were 1.27 and 1.08 per 10 μg/m3 increase, respectively. The oldest-old experienced a much lower mortality risk from air pollution compared to the young-old. The mortality risk of PM2.5 was higher in areas with higher annual average temperatures. The adjustment of road density considerably intensified the association between NO2 and mortality. The ambient PM2.5 and O3 levels in China exceeded the WHO AQG target substantially. Multiple pollutants coexposure, confounding, and modification of the district economic and climate factors should not be ignored in the association between air pollution and mortality.

Link: https://doi.org/10.1021/envhealth.3c00106

Parkinson's disease arises from the spread of misfolded α-synuclein and associated toxicity. α-synuclein is one of the few proteins in the body capable of misfolding in ways that encourage other molecules of the same protein to also misfold, forming solid aggregates and a surrounding halo of altered biochemistry that changes cell behavior for the worse, or kills those cells. The immune system is capable of mounting a defense against this sort of issue, but as noted here, the immune response to protein aggregates in the central nervous system is dampened by an increasing burden of cellular senescence and inflammatory signaling in the supporting cells of the brain.

Parkinson's disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra. Aging is a significant risk factor for PD. The accumulation of senescent glial cells in the aged brain contributes to PD progression by inducing chronic neuroinflammatory processes. However, although the insufficient degradation of α-syn aggregates results in PD deterioration, the possible alteration in the ability of α-syn clearance in senescent glia has received little attention.

In this study, we investigated how aging and glial senescence affect the capacity of α-syn clearance. We found that following the intra-striatal injection of human α-syn (hu-α-syn) preformed fibril, hu-α-syn pathology persisted more in aged mice compared with younger mice and that aged microglia exhibited greater accumulation of hu-α-syn than younger microglia. Moreover, in vitro assay revealed that the clearance of hu-α-syn was primarily dependent on the autophagy-lysosome system rather than on the ubiquitin-proteasome system and that the capacity of hu-α-syn clearance was diminished in senescent glia because of autophagy-lysosome system dysfunction. Overall, this study provides new insights into the role of senescent glia in PD pathogenesis.

Link: https://doi.org/10.1038/s41420-024-01816-8

The circulating level of brain-derived neurotrophic factor (BDNF) is a widely-researched target for intervention. Increased BDNF seems to be wholly beneficial, particularly in its effects on neurogenesis, the production of new neurons and their integration into existing neural networks in the brain. Neurogenesis declines over the course of adult life, and is necessary to the function of memory and maintenance of brain tissue. Circulating BDNF, where levels also decline with age, might be the most convenient of the available mechanisms with which to affect neurogenesis. It can be increased by exercise, butyrate supplementation, and by interventions targeting the gut microbiome. Separately, BDNF also appears to influence muscle aging, reduce inflammatory microglial activation, increase dopamine levels, and slow metabolic aging, among other effects.

If exercise can increase circulating BDNF, what about intermittent fasting and calorie restriction? There is some evidence for this to work. In today's open access paper, researchers review the literature and find the results to be very varied, however. This suggests that either specific protocols are needed, or other factors interact meaningfully with reduced calorie intake, or both. It remains the case that both intermittent fasting and calorie restriction have been demonstrated to be great for long-term health, but it is always interesting to find evidence for a mechanism that may not be improved by these practices.

Effect of Calorie Restriction and Intermittent Fasting Regimens on Brain-Derived Neurotrophic Factor Levels and Cognitive Function in Humans: A Systematic Review

The potential positive interaction between intermittent fasting (IF) and brain-derived neurotrophic factor (BDNF) on cognitive function has been widely discussed. This systematic review tried to assess the efficacy of interventions with different IF regimens on BDNF levels and their association with cognitive functions in humans. Interventions with different forms of IF such as caloric restriction (CR), alternate-day fasting (ADF), time-restricted eating (TRE), and the Ramadan model of intermittent fasting (RIF) were targeted.

A systematic review was conducted for experimental and observational studies on healthy people and patients with diseases published from January 2000 to December 2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statements (PRISMA) for writing this review. Sixteen research works conducted on healthy people and patients with metabolic disorders met the inclusion criteria for this systematic review. Five studies showed a significant increase in BDNF after the intervention, while five studies reported a significant decrease in BDNF levels, and the other six studies showed no significant changes in BDNF levels due to IF regimens. Moreover, five studies examined the RIF protocol, of which, three studies showed a significant reduction, while two showed a significant increase in BDNF levels, along with an improvement in cognitive function after RIF.

The current findings suggest that IF has varying effects on BDNF levels and cognitive functions in healthy, overweight/obese individuals and patients with metabolic conditions. However, few human studies have shown that IF increases BDNF levels, with controversial results. In humans, IF has yet to be fully investigated in terms of its long-term effect on BDNF and cognitive functions. Large-scale, well-controlled studies with high-quality data are warranted to elucidate the impact of the IF regimens on BDNF levels and cognitive functions.

Researchers here report on the results of a drug screen focused on mimicking the transcriptional changes that occur in a number of interventions shown to modestly slow aging in short-lived species. They find an inhibitor of histone deacetylases HDAC1 and HDAC2 achieves this outcome, and note that in mice this drug candidate can produce positive changes in a number of measures of tissue function. Further studies will have to explore longer-term effects, dosing, and side-effects. Histone decacetylases influence the structure of the nuclear genome, and thus also influence gene expression quite broadly. Understanding how and why benefits result from this drug candidate will be a long-term undertaking. Further one should probably expect a sizable chance of undesirable side-effects, given what is known of this class of small molecule drug. Other histone deacetylases are under development for treatment of a range of conditions. Inhibition of HDAC1 seems positive here, but other research has shown that upregulation is beneficial in the context of aging neurons.

Aging increases the risk of age-related diseases, imposing substantial healthcare and personal costs. Targeting fundamental aging mechanisms pharmacologically can promote healthy aging and reduce this disease susceptibility. In this work, we employed transcriptome-based drug screening to identify compounds emulating transcriptional signatures of long-lived genetic interventions. We discovered compound 60 (Cmpd60), a selective histone deacetylase 1 and 2 (HDAC1/2) inhibitor, mimicking diverse longevity interventions.

In extensive molecular, phenotypic, and bioinformatic assessments using various cell and aged mouse models, we found Cmpd60 treatment to improve age-related phenotypes in multiple organs. Cmpd60 reduces renal epithelial-mesenchymal transition and fibrosis in kidney, diminishes dementia-related gene expression in brain, and enhances cardiac contractility and relaxation for the heart. In sum, our two-week HDAC1/2 inhibitor treatment in aged mice establishes a multi-tissue, healthy aging intervention in mammals, holding promise for therapeutic translation to promote healthy aging in humans.

Link: https://doi.org/10.1016/j.isci.2023.108681

The hundreds of mitochondria present in every cell are primarily responsible for generating adenosine triphosphate, a chemical energy store molecule used to power cell operations. Mitochondria are the descendants of ancient symbiotic bacteria, and carry a small circular genome, the mitochondrial DNA. They replicate as needed, can fuse together and swap component parts, and damaged mitochondria are removed by cell maintenance processes. Mitochondrial function declines with age for a variety of reasons that include damage to mitochondrial DNA and changes in the expression of genes involved in replication, fusion, and quality control. How much of a contribution does this make to muscle aging? To determine that will require therapies such as mitochondrial transplantation that can repair the mitochondrial dysfunction of aging without changing other aspects of aged tissues.

Healthy lifestyles, such as those that include regular physical activity and a balanced diet, are a powerful means to prevent chronic disease and age-related functional decline. A common denominator of health improvements resulting from good exercise and diet habits is the optimization of metabolic processes. These processes include energy metabolism and, thus, the activity of mitochondria. Mitochondria represent hubs not only of cellular metabolism but also of the regulation of redox states, inflammatory response, and immunity, as well as many other cellular features. Mitochondria have emerged as highly flexible organelles that, quickly - and sometimes persistently - adapt to changing conditions in response to systemic or cellular challenges. Next to exercise and diets that promote mitochondrial health, transient exposures to environmental stressors, such as to altitude/hypoxia or extreme temperatures, also induce mitochondrial adaptations.

In this paper, we discuss how different systemic and cellular challenges trigger specific and overlapping mitochondrial responses that - under the right conditions - may translate into protective mitochondrial adaptations. We specifically focus on adaptations in skeletal muscle and sarcopenia, the age-related loss of skeletal muscle mass, strength, and function. Such responses rely on mechanisms such as mitochondrial stress responses and quality control; therefore, these mechanisms are believed to be required to maintain mitochondrial health. The resulting adaptations increase the capacity of mitochondria to respond to future stressors (e.g., altered oxygen or substrate availability), which otherwise might trigger pathological processes. Considering potential synergistic/anti-synergistic and complementary/competitive effects among lifestyle factors and environmental challenges on mitochondria, we argue that recommendations can be developed to increase performance, prevent sarcopenia, and improve healthy aging.

Link: https://doi.org/10.3389/fpubh.2023.1330131

Partial epigenetic reprogramming emerges from the intersection of understanding how cells behave in cancerous tissue and during embryonic development. In the developing embryo there is a point at which adult germline cells convert themselves into embryonic stem cells, discarding forms of damage and dysfunction characteristic of adult cells and restoring a youthful pattern of the epigenetic markers attached to the genome that control its shape in the cell nucleus and thus gene expression. Some of the genes involved are known to also operate in cancers, in which replication and reprogramming runs wild, but which use many of the same mechanisms as the embyro.

Given exploratory work to date, it seems possible to pick apart the regulatory systems controlling (a) change of cell type via dedifferentiation, and (b) restoration of youthful epigenetic markers. That second item is highly desirable. If researchers could reset the epigenetics of aged cells, they would become more youthful. Given enough cells reset in this way, tissues and organs would become more youthful in function. Some forms of age-related molecular damage can't be repaired in this way, such as persistent metabolic waste or nuclear DNA damage, but evidence from studies of epigenetic reprogramming in aged mice suggest that there are sizable gains that can be achieved via this approach, provided that cancerous transformation of cells can be kept at bay.

One might argue that given the existence of Altos Labs ($3 billion), Retro Biosciences ($180M), and at least another $100M in investment in various epigenetic reprogramming ventures, there is little need to advocate for epigenetic reprogramming as a road to rejuvenation. That road will be traveled in the years ahead regardless of the thoughts that any of the rest of us might have on the matter. The funding is there, a great many researchers are working on the challenges involved, the big questions will be answered, initial therapies will be cautiously deployed in small parts of the body such as the eye, and whether or not expression of reprogramming factors throughout much of the body, via small molecules or gene therapy, is viable as a basis for rejuvenation therapies will be much more clear a few years from now.

Epigenetic Reprogramming as a Key to Reverse Ageing and Increase Longevity

The pursuit for the fountain of youth has long been a fascination amongst scientists and humanity. Ageing is broadly characterized by a cellular decline with increased susceptibility to age-related diseases, being intimately associated with epigenetic modifications. Recently, reprogramming-induced rejuvenation strategies have begun to greatly alter longevity research not only to tackle age-related defects but also to possibly reverse the cellular ageing process. Hence, in this review, we highlight the major epigenetic changes during ageing and the state-of-art of the current emerging epigenetic reprogramming strategies leveraging on transcription factors. Notably, partial reprogramming enables the resetting of the ageing clock without erasing cellular identity. Promising chemical-based rejuvenation strategies harnessing small molecules, including DNA methyltransferase and histone deacetylase inhibitors are also discussed.

Moreover, in parallel to longevity interventions, the foundations of epigenetic clocks for accurate ageing assessment and evaluation of reprogramming approaches are briefly presented. Going further, with such scientific breakthroughs, we are witnessing a rise in the longevity biotech industry aiming to extend the health span and ideally achieve human rejuvenation one day. In this context, we overview the main scenarios proposed for the future of the socio-economic and ethical challenges associated with such an emerging field. Ultimately, this review aims to inspire future research on interventions that promote healthy ageing for all.

Numerous intriguing questions remain unanswered. (1) What are the specific molecular mechanisms behind epigenetic dysfunction that contribute to the ageing process and how do these correlate with the different hallmarks of ageing? (2) To what extent can the current in vitro aged animal models be translatable to the human ageing process in its entirety? Will emerging humanized in vitro 3D models such as organoids accelerate longevity research? (3) Realistically, how far are we from reprogramming-induced epigenetic rejuvenation interventions in human clinical trials? Will these rejuvenate organs and even the entire human body? Could these prevent and eradicate ageing-related diseases safely? (4) In the future, could epigenetic reprogramming be a routine medical procedure to reverse the biological age and extend human healthspan? Would these interventions be effective in both young and elderly individuals? How far could we go? (5) How reliable could epigenetic clocks be in research and clinical settings for developing and prescribing novel healthspan-prolonging interventions? (6) Will legislative and policy frameworks be able to keep pace with the scientific breakthroughs in the young science of anti-ageing treatments? How will bioethicists, society, and medical professionals perceive these emerging findings?

The hallmarks of aging are exactly that, hallmarks. They are not intended to be a list of causative mechanisms, though it appears that some people take it that way, particularly if it is supportive to their research and development program choices. Some of the hallmarks of aging overlap with the Strategies for Engineered Negligible Senescence (SENS) list of proposed causative mechanisms of aging, and the hallmarks paper itself clearly owes much to earlier SENS publications, as well as parallel proposals such as the Seven Pillars of Aging. It is important to target causes rather than consequences when it comes to aspects of aging, as only the treatment of causes is likely to be effective. The field is overdue a more broad, high-profile critique and consideration of the hallmarks of aging from the perspective of identifying causative mechanisms for intervention, rather than simply describing aging.

In a recent review article researchers conducted an exhaustive literature review and described an updated 12 hallmarks of aging. The updated model of aging comprehensively captures the key characteristics of the aging phenotype and incorporates new pathways that play a crucial role in age-related processes. Although the updated hallmarks of aging provide a useful framework for describing the phenotype of aging, aging itself is a result of mechanistically complex and interrelated processes that happen during the lifespan of the organism. Here, I propose to shift the focus from a systematic description and categorization of the hallmarks of aging to a model that separates the early, molecular origins of changes from cellular and tissue responses and represents the sequential and causative character of changes in aging. The proposed model aims to prompt discussion among the aging research community, guide future efforts in the field, and provide new ideas for investigation.

When the original 9 hallmarks of aging were first introduced in 2013, little was known about the mechanisms of aging. Since then, many research groups have described various mechanisms underlying this process, introducing the concept of the sequential character of changes in time and the molecular basis of the process. Therefore, I believe that the hallmarks of aging will benefit from the inclusion of information of temporal and sequential character of the process of aging. The aging process is commonly divided into early and late events, with a clear distinction between aging phenotypes and the underlying molecular events. Aging encompasses molecular, physiological, and phenotypic changes with different clinical relevance and different short-term or long-term outcomes if targeted using pharmacological interventions. Therefore, I propose a "three-wheeled gears" model to describe the early (upstream), intermediate, and late (downstream) events.

Any type of stress/disturbance can induce epigenetic changes, transcriptional noise, nuclear DNA damage and mitochondrial DNA damage, loss of cell membrane integrity, and oxidative stress, among other molecular disturbances. Intermediate events of aging encompass cellular responses to stress-induced molecular alterations and include activation of inflammation, proteostasis, autophagy, senescence, establishing energy homeostasis, and rewiring of cellular metabolism. If not resolved, molecular and cellular alterations due to repeated stress throughout the life of the individual trigger late events of aging, which manifest as aging phenotypes. Late events of aging result in progressive deterioration of organ function and include stem cell exhaustion, organ dysfunction, loss of tissue integrity, immune system dysfunction, for example, chronic low levels of inflammation, and alterations in tissue-tissue interactions and cell-cell communication. Molecular, cellular, and phenotypic processes of aging are interconnected, and progression in one process induces the progression of all other processes.

At present, investigational therapeutic approaches targeting aging phenotypes are geared mostly toward reverting aging symptoms rather than targeting the underlying molecular and cellular mechanisms. However, recognizing the aging phenotype is crucial for deciphering the mechanisms underlying aging and age-related diseases. We cannot fully delineate complex biological processes such as aging without addressing the molecular and cellular mechanisms that contribute to the different characteristics of aging and without dissecting the temporal and causal sequence of events.

Link: https://doi.org/10.59368/agingbio.20230011

Some of the benefits of fasting in later life derive from suppression of the chronic, unresolved inflammatory signaling characteristic of old age. As is usually the case in such matters, how much of the overall beneficial effect of fasting on long-term health, mortality, and life expectancy is due to this mechanism remains an open question. Similarly, while researchers here focus on one specific way in which inflammation is suppressed following fasting, via an interaction with the inflammasome, whether this specific interaction is a large or a small contribution to the whole remains to be determined, even given the interesting comparison with nonsteroidal anti-inflammatory drugs.

Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated.

Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages.

Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

Link: https://doi.org/10.1016/j.celrep.2024.113700

Karl Pfleger is one of the more prolific angel investors in the longevity industry. Naturally he is an investor in Repair Biotechnologies, the company that I co-founded with Bill Cherman and which is currently focused on a gene therapy approach to reversal of atherosclerosis. In addition to his investment and conference-going activities, Pfleger runs the very useful Aging Biotech Info resource, which has expanded from the starting point of a list of companies in the longevity industry to its present state of listing of a great many more items: conferences, books, blogs, interventions, diagnostics, and so forth. In the podcast interview linked below, topics include epigenetic clocks and the need for improvement in measurement of biological age, current interventions, and the state of the field as a whole.

Unlocking the Secrets of Lifespan Extension With Karl Pfleger

I worked at Google for about a decade doing practical, big data, machine learning stuff and then I decided to refocus my attention on things that would most help the world, most help the most people in the world. And cursory analysis suggested that besides the poorest of the poor, you know, living in sub-Saharan Africa and places like that on less than $2 a day, the the highest leverage other thing in the world was to fight against the aging process, because aging is what kills the vast majority of people, 70% globally, 92 and a half percent plus in Western developed countries. That's really a science and technology play more than a lobbying political play. So I decided and also I lived in the San Francisco Bay Area, which was kind of ground zero for that science and the biotech and the entrepreneurship and so I just basically whole hog switched fields and have just been ramping up the bio knowledge ever since. I started with philanthropy then got into investing and I'm also doing a whole bunch of other things involved in community building and information dissemination.

I started in the field in the mid 2010s, there was it was much smaller field. It's grown considerably, which is great. It's still a very small corner of the overall biotech world. But but it's growing because there's an inevitable logic of treating these biological causes that underlie so many different bad conditions. But when I got into the field, it was small, but there was still quite a lot written about it. There were books and there were blogs, and it was a lot of blobs of text, and there were some companies already in the space, and I decided to get into investing in the 2016-ish and started investing in biotech companies in 2017. One of the things I did once I started doing that was every time I went to a conference or an event where any company was mentioned, I wrote it down on the list and quickly my list of companies was 100 to 120 companies.

You know, I hadn't investigated each one, so I wasn't sure whether I counted each one as, you know, really being an aging and longevity related company or not. But so it was all new. So I didn't have an exact count 100, 120. And I kept reading these stories of people talking who were giving an overview of the whole aging or longevity field, talking about how there's 30 companies where there's 40 companies or usually there's 25 companies, something like that. And I was like, wow, these people don't know about a lot of the companies. And I would talk to the professors who work in the field. So just north of me here in San Francisco, there's a place called the Buck Institute for Research on Aging. It's the largest independent. It's essentially a sort of Ivy League Stanford or MIT level biology department, sitting all by itself without the rest of the university around it. Every single one of the 20 pitches are all focused specifically on the biology of aging. And that was the most ground zero at academia for aging stuff. And they didn't even realize how many companies there were at the moment.

So I decided that instead of keeping my list of companies as sort of some kind of internal secret to make my investing better, I would just open source it, essentially. And so I put it together and put it on this website. I called it Aging Biotech Info, and I made it just pro-bono, open, free for everybody. And it's worked pretty well. The goals, the use cases I envisioned when I started it were I wanted the post-docs and Ph.D. students and even professors to realize they had an exit ramp from academia if they wanted to do something else. As they could start a company. And I wanted the investors, the tech people in Silicon Valley, the venture capital groups, to realize that they should be putting more than a few percent in this field, that there was a lot more going on than they thought, and they should be ramping up to five, ten, 15% of their mostly tech portfolios, which they have done. I'll never know how much this website contributed to any of that, but that has certainly helped.

Considerable progress has been made in recent years in mapping the pathways by which cerebrospinal fluid drains from the brain into the body, many of which were only recently discovered. The present consensus is that the progressive loss of this drainage with advancing age is likely important in the development of neurodegenerative conditions, allowing molecular waste such as amyloid-β to build up in the brain. Researchers here discuss a new branch of the system of cerebrospinal fluid drainage that passes behind the nose. Like the related cribriform plate pathway, this makes it off interest in the development of Alzheimer's disease, as the pathology of this condition starts in a nearby region of the brain.

In our brains, waste products generated as byproducts of metabolic activity are expelled through cerebrospinal fluid (CSF). Accumulation of waste in the brain, if not properly expelled, can damage nerve cells, leading to impaired cognitive function, dementia, and other neurodegenerative brain disorders. Hence, the regulation of CSF production, circulation, and drainage has long been a focus of scientific attention, especially in relation to age-related conditions like Alzheimer's disease and other neurodegenerative diseases.

The brain produces around 500 mL of this fluid per day, which is drained from the subarachnoid space. Among the known drainage routes are lymphatic vessels around the cranial nerves and the upper region of the nasal cavity. Despite well-documented evidence of lymphatics aiding CSF clearance, identifying the exact anatomical connections between the subarachnoid space and extracranial lymphatics has posed a challenge due to their extremely complex structure.

Researchers tackled this problem using transgenic mice with lymphatic fluorescent markers, microsurgeries, and advanced imaging techniques. Their efforts revealed a detailed network of lymphatic vessels at the back of the nose that serves as a major hub for CSF outflow to deep cervical lymph nodes in the neck. These lymphatics were found to have distinct features, including unusually shaped valves and short lymphangions. The study also demonstrated that pharmacological activation of the deep cervical lymphatics enhanced CSF drainage in mice. The researchers were able to successfully modulate cervical lymphatics using phenylephrine (which activates α1-adrenergic receptors, causing smooth-muscle contraction) or sodium nitroprusside (which releases nitric oxide, inducing muscle relaxation and vessel dilation). Importantly, this feature was preserved during aging, even when the nasopharyngeal lymphatic plexus had shrunk and was functionally impaired.

Link: https://www.ibs.re.kr/cop/bbs/BBSMSTR_000000000738/selectBoardArticle.do?nttId=24483

Individual wealth correlates with life expectancy, with an effect size that is in the same ballpark as those related to lifestyle choices involving exercise, diet, and consequences thereof. It remains unclear as to why wealth correlates with life expectancy. It is a part of a tangled web of correlations including intelligence, education, social status, personality traits, access to and ability to use medical services, as well as the suspicion that genetic associations with at least some of those line items (largely intelligence) may also independently affect health. Theorizing is easy, but assessing the relative contributions of the various proposed mechanisms is a challenge; proposing to fix the issue by top-down redistribution is naive for a number of reasons, perhaps the least of which being that absent an understanding of the mechanisms there is no guarantee that it would work.

This longitudinal cohort study analyzed the association between wealth and survival among participants in the Health and Retirement Study (1992-2018), a nationally representative panel study of middle-aged and older (≥50 years) community-dwelling, noninstitutionalized US adults. The data analysis was performed between November 15, 2022, and September 24, 2023. Household wealth was assessed on study entry, calculated as the sum of all assets minus the value of debts and classified into deciles. Weibull survival models were used to estimate the association between per-person wealth decile and survival, adjusting for age, sex, marital status, household size, and race and ethnicity. Changes in longevity that might occur under alternative wealth distributions were then estimated.

The sample included 35,164 participants (mean age at study entry, 59.1 years). The hazard of death generally decreased with increasing wealth, wherein participants in the highest wealth decile had a hazard ratio of 0.59 for death compared with those in the lowest decile, corresponding to a 13.5-year difference in survival. A simulated wealth distribution of perfect equality would increase populationwide median longevity by 2.2 years, fully closing the mortality gap between the US and the OECD average. A simulated minimum inheritance proposal would increase populationwide median longevity by 1.7 years; a simulated wealth distribution similar to Japan's would increase populationwide median longevity by 1.2 years; and a simulated baby bonds proposal would increase populationwide median longevity by 1.0 year.

Link: https://doi.org/10.1001/jamainternmed.2023.7975

Telomerase acts to extend telomeres, the repeated DNA sequences at the ends of chromosomes. With every cell division, some of the telomere repeats are lost. Cells with critically short telomeres become senescent or undergo programmed cell death, having reached the Hayflick limit on replication. Some cells employ telomerase to adjust the countdown of telomere length. In humans, only stem cells use telomerase. In other species, such as mice, telomerase is much more widely expressed. There has been some interest in the research community in upregulation of telomerase as a way to improve stem cell and tissue function in old age.

One of the points of risk in bringing telomerase gene therapies to the clinic is that while the results to date in mice have been impressive, gene therapies producing extended life, improved function, reduced cancer incidence, mice have very different telomere dynamics from humans. Will the risk of extending the functional life of damaged, potentially cancerous somatic cells be offset by improved immune function in humans as it seems to be in mice? While some number of people have undergone telomerase gene therapy, largely via medical tourism, results for most of those patients will never be published, and long-term data on cancer risk will in any case take years to emerge.

In today's open access paper, researchers report on the development of a mouse lineage with a humanized telomerase gene and more human-like telomere dynamics. This will be a useful tool in the continued development of telomerase gene therapies. If telomerase gene therapy in this lineage turns out to produce much the same benefits as it does in wild type mice, with particular attention to cancer incidence, then one could be more convinced that risks in human patients are lower.

Humanization of the mouse telomerase gene reset telomeres to human length

Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert, wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene.

Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert-knockout mice. Through successive intercrosses of Tert(h/-) mice, telomere length progressively declined, stabilizing below 10-kb. Tert(h/h) mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Tert(h/h) mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Terth/h mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres.

Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.

The aging immune system exhibits a declining ability to destroy pathogens and dysfunctional, harmful cells. This is known as immunosenescence. There are ways to assess immune cell populations and their characteristics to measure the degree of immunosenescence, but this is comparatively costly and cannot be used on banked samples. Researchers here ask whether combinations of circulating proteins can instead be used to assess the degree of immunosenescence from a blood sample, and propose a few such biomarkers based on their analysis.

Inflammaging, the characteristics of immunosenescence, is characterized by continuous chronic inflammation that could not be resolved. It not only affects older people but can also occur in young individuals, especially those suffering from chronic inflammatory conditions such as autoimmune disease, malignancy, or chronic infection. This condition led to altered immune function and as consequent immune function is reduced. Detection of immunosenescence has been done by examining the immune risk profile (IRP), which uses flow cytometry. These tests are not always available in health facilities, especially in developing countries and require fresh whole blood samples. Therefore, it is necessary to find biomarkers that can be tested using stored serum to make it easier to refer to the examination.

Here we proposed an insight for soluble biomarkers which represented immune cells activities and exhaustion, namely sCD163, sCD28, sCD80, and sCTLA-4. Those markers were reported to be elevated in chronic diseases that caused early aging and easily detected from serum samples using ELISA method, unlike IRP. Therefore, we conclude that these soluble markers are beneficial to predict the pathological condition of immunosenescence.

Link: https://doi.org/10.1186/s12979-023-00405-0

CISD2 expression declines with age, while upregulation of CISD2 expression has been shown in mice to improve liver function and extend life span. This strategy is expected to have broad effects on function in many tissues beyond the liver. At least some of those benefits result from an increase in the efficiency of the complex cell maintenance processes of autophagy, recycling damaged and unwanted proteins and cell structures. As is the case for other approaches to slowing aging that function via autophagy, CISD2 upregulation has the effect of reducing senescent cell burden and suppressing the harmful senescence-associated secretory phenotype (SASP). Researchers here demonstrate this benefit in aged skin.

CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy.

We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging.

Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice.

Link: https://doi.org/10.1186/s12929-024-01005-w

Bone is constantly remodeled throughout life. The extracellular matrix making up bone tissue is continually broken down by osteoclast cells and built up by osteoblast cells. In youth, these activities are balanced. With aging, however, the activity of osteoclast cells progressively outweighs the activity of osteoblast cells. The consequence is an ever greater loss of bone mineral density leading to osteoporosis. This process is also found in the bone loss characteristic of advanced periodontitis. There are many contributing factors leading to the imbalance in bone remodeling, and it isn't all that clear as to which of them are more or less important than the others, even given the existence of treatments, such as bisphosphonates, that can slow the progression of osteoporosis. There is certainly a need for better therapies, those with the ability to dramatically increase bone mineral density.

In today's open access paper, researchers discuss the role of DEL-1 in bone loss related to periodontitis. They demonstrate an approach to upregulation of DEL-1 expression, showing that it can regenerate bone in this context of gum disease. The researchers do a good job of laying out the various interactions along the way, and demonstrate that the treatment requires DEL-1 to function. Thus DEL-1 is the critical link, and expression of DEL-1 declines with age, perhaps an important contribution to loss of bone mineral density. This mechanism may additionally be worth exploring in the broader context of all bone loss experienced with age. Whether that is the case remains to be seen.

A novel macrolide-Del-1 axis to regenerate bone in old age

Development endothelial locus-1 (DEL-1) is a homeostatic protein secreted by tissue-resident cells in the gingiva and the periodontal ligament (PDL), endothelial and mesenchymal stromal/stem cells (MSCs) and some macrophage subsets, and contributes to inflammation resolution and tissue repair. Specifically, during the resolution phase of experimental periodontitis in mice, DEL-1 promotes efferocytosis and the emergence of the macrophage pro-resolving phenotype as well as stimulating alveolar bone regeneration. The pro-regenerative function of DEL-1 is largely independent of its efferocytic/pro-resolving function and involves activation of a β3 integrin-FAK-ERK1/2-RUNX2 pathway in osteoprogenitor cells. Alveolar bone regeneration fails in DEL-1-deficient mice or in mice that express a DEL-1 point mutant that cannot bind β3 integrins. The expression of DEL-1 is severely diminished in old age, both in mice and humans.

Given that DEL-1 levels decline severely in old age and mice ≥18 months of age are DEL-1 deficient, it is important to develop potential therapeutic approaches to stimulate DEL-1 expression, thereby restoring the levels of this important homeostatic protein in the elderly. We have recently shown that the macrolide antibiotic erythromycin (ERM) - but not other antibiotics, such as penicillin and josamycin - stimulates the production of DEL-1 in vascular endothelial cells. Specifically, erythromycin interacts with the growth hormone secretagogue receptor (GHSR) and activates JAK2 and p38 MAPK signaling, leading to C/EBPβ-dependent DEL-1 expression. Moreover, systemic erythromycin treatment in mice increased DEL-1 expression in the PDL, which connects the tooth to the surrounding alveolar bone. The PDL of humans and animals, including mice, contains a mostly perivascular MSC niche involved in periodontal tissue regeneration and includes progenitor cells that can differentiate into osteoblasts.

We show that erythromycin and other macrolides restore DEL-1 expression in old mice and promote regeneration of bone lost due to naturally occurring, aging-related periodontitis. The same treatment increased the bone mass in the femurs of old mice. Importantly, EM-523, a non-antibiotic derivative of erythromycin, that retains the ability to activate a homolog of the GHSR, motilin receptor, reproduced the DEL-1-dependent effect of erythromycin on bone regeneration. Mechanistically, macrolide and EM-523 treatments induced the formation of new bone by upregulating alkaline phosphatase (ALP) activity and the expression of osteogenic genes in periodontal tissue while reducing the number of osteoclasts, thereby favorably influencing the osteogenesis/osteoclastogenesis balance. Periodontal bone lost due to periodontitis has limited capacity for regeneration even after standard treatment (scaling and root planing) and surgical periodontal therapy, especially in elderly patients. Therefore, the non-antibiotic compound EM-523 may represent a safe, effective, and affordable new approach to regenerate bone lost due to periodontitis in humans and perhaps for increasing the mineral content of the skeletal bone in the elderly.

Researchers here investigate age-related changes correlating with loss of working memory. They work with mice, but produce results that line up with observations made in other species. How neural circuits function is one distinct way of looking at the brain. Like all such approaches, it is challenging to connect it to other distinct views of the aging brain, such as proteomic or transcriptomic or cell behavior or signaling changes, or the accumulation of specific forms of age-related molecular damage. Measuring one aspect of a complex system is one thing, figuring out how many different aspects fit together into a web of interacting causes and consequences is quite another.

Cognitive aging is the natural and gradual decline in cognitive function that occurs as people age and emerges as a major challenge for maintaining quality of life and employment. It is hence crucial to understand the neurobiology underlying cognitive aging in detail. Working memory (WM) decline is a fundamental aspect of cognitive aging and has the earliest onset among age-related cognitive deficits. Executive function is susceptible to aging. How aging impacts the circuit-level computations underlying executive function remains unclear. Using calcium imaging and optogenetic manipulation during memory-guided behavior, we show that working-memory coding and the relevant recurrent connectivity in the mouse medial prefrontal cortex (mPFC) are altered as early as middle age.

Population activity in the young adult mPFC exhibits dissociable yet overlapping patterns between tactile and auditory modalities, enabling crossmodal memory coding concurrent with modality-dependent coding. In middle age, however, crossmodal coding remarkably diminishes while modality-dependent coding persists, and both types of coding decay in advanced age. Resting-state functional connectivity, especially among memory-coding neurons, decreases already in middle age, suggesting deteriorated recurrent circuits for memory maintenance. Optogenetic inactivation reveals that the middle-aged mPFC exhibits heightened vulnerability to perturbations. These findings elucidate functional alterations of the prefrontal circuit that unfold in middle age and deteriorate further as a hallmark of cognitive aging.

Link: https://doi.org/10.1038/s41467-023-43142-0

Cellular senescence is protective against cancer, at least initially. When cells become senescent due to potentially cancer-inducing damage, shutting down replication and secreting pro-inflammatory signals reduces the risk of cancer and attracts the immune system to clear out other potentially cancerous cells that have not become senescent. When senescent cells linger in larger numbers, however, they begin to aid cancer by changing the environment into one that favors the growth of cancerous tissue. Thus clearing senescent cells in conjunction with traditional cancer treatments is more effective for patients than the treatment on its own. Additionally, the established approaches of chemotherapy and radiotherapy produce a lasting burden of senescent cells in the course of killing the cancer. This harms patients, increasing their risk of age-related disease and reducing life expectancy, but senolytic therapies to clear those senescent cells may remove this well-established cost to successful cancer treatment.

Cancer treatments, including chemotherapy, in addition to killing a large number of tumour cells, also result in the generation of senescent tumour cells. While senescent cells do not reproduce, they do, unfortunately, generate a favourable environment for the expansion of tumour cells that may have escaped the effects of the chemotherapy and eventually result in tumour regrowth. Researchers have described how cancer cells that have become senescent after chemotherapy activate the PD-L2 protein to protect themselves from the immune system while recruiting immune suppressor cells. The latter creates an inhibitory environment that impairs the ability of lymphocytes to kill cancer cells.

Based on these findings, scientists wondered what would be the effect of inactivating PD-L2. Interestingly, senescent cells lacking PD-L2 are rapidly eliminated by the immune system. This intercepts the capacity of senescent cells to create an immunosuppressive environment and, as a result, lymphocytes retain their full capacity to kill those cancer cells that may have escaped the effects of chemotherapy. "By blocking PD-L2 in mouse models, we have seen that chemotherapy is more effective against cancer. This finding paves the way to consider the use of a potential PD-L2 inhibitor as an adjuvant in the treatment of this disease."

Link: https://www.irbbarcelona.org/en/news/scientific/chemotherapy-becomes-more-efficient-when-senescent-cells-are-eliminated