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Telomere Length as a Target for Therapy
https://www.fightaging.org/archives/2024/02/telomere-length-as-a-target-for-therapy/
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.
An Update on Progress Towards Treating Atherosclerosis at Cyclarity
https://www.fightaging.org/archives/2024/02/an-update-on-progress-towards-treating-atherosclerosis-at-cyclarity/
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.
Why Don’t Biotech Investors Run Replication Studies Before Investing?
https://www.fightaging.org/archives/2024/02/why-dont-biotech-investors-run-replication-studies-before-investing/
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.
NPTX2 Involved in Neurodegeneration Driven by TDP-43 Aggregation
https://www.fightaging.org/archives/2024/02/nptx2-involved-in-neurodegeneration-driven-by-tdp-43-aggregation/
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.
What is Known of the Contribution of Cellular Senescence to Osteoporosis
https://www.fightaging.org/archives/2024/03/what-is-known-of-the-contribution-of-cellular-senescence-to-osteoporosis/
The vast majority of senescent cells are produced when somatic cells reach the Hayflick limit to cell division, their telomeres shortened to a point at which they either self-destruct or enter the senescent state. Damage due to mutation or cytotoxic compounds can also induce senescence, as can the regenerative processes following injury. Senescent cells cease replication, become larger, and change their behavior in many other ways. Senescent cells secrete a pro-growth, pro-inflammatory mix of signals, the senescence-associated secretory phenotype (SASP), that attracts the attention of immune cells capable of destroying senescent cells, but also encourages nearby cells to become senescent.
Throughout much of life, senescence serves as a way to remove damaged cells and suppress the risk of cancer, but this is only the case because these cells are promptly cleared as they arise. Unfortunately, the immune system becomes ever less capable with advancing age, and senescent cells accumulate as the pace of create outstrips the pace of destruction. When senescent cells are constantly present, the SASP turns from helpful to harmful. It induces chronic inflammation, disrupts tissue structure and function, and contributes meaningfully to the onset and progression of all of the common age-related conditions. One of those conditions is osteoporosis, the age-related loss of bone density and the subject of today’s open access paper.
Recent advances in senescence-associated secretory phenotype and osteoporosis
Although aging is an uncontrollable process, it is possible to mitigate age-related disorders by modifying the fundamental aging mechanisms. Cellular senescence is one of the mechanisms that can manifest in various biological processes via senescence-associated secretory phenotypes, SASPs. SASPs contribute to releasing cytokines and chemokines that promote local and systemic inflammatory responses, immune system activation, tissue damage, fibrosis, apoptosis, and malfunction. In addition, SASP can cause amplification of localized and systemic senescence via paracrine or endocrine pathways.
Osteoporosis (OP) has emerged as a significant health risk for individuals aged 50 and beyond. As the population ages, there are more instances of osteoporosis and fragility fractures, which puts an increasing strain on the health system. Osteoporosis formation and occurrence in aging are associated with deficient hormone levels, imbalanced bone remodeling, and a restricted number of osteoblasts, osteocytes, and their progenitor cells. Connecting the dots directly to osteoporosis, it is clear that the build-up of senescent cells (SCs) and the overexpression of SASPs in the bone microenvironment are closely linked to the etiology of this illness. In addition, senescent cells have also been shown to be present in the setting of radiotherapy-induced bone loss, and bone biopsy samples from elderly postmenopausal women. Current studies have found that targeting senescent bone cells in the bone and modulating SASP activity can promote bone remodeling and alleviate the symptoms of OP.
Many studies indicate that anti-senescence therapy drugs may have a role in treating osteoporosis associated with aging, radiation, diabetes, estrogen shortage. Nowadays, essential senescence treatment drugs can be categorized into two groups. One is the senolytic approach, which eliminates senescent cells by targeting the apoptotic pathway of senescent cells. The other one is senomorphic technique that targets SASP without influencing cell death. Senolytic medicines such as Dasatinib (D), quercetin (Q), D + Q, Navitoclax (ABT263), BCL-XL inhibitor, HSP90 inhibitor, and ABT-737 are utilized in animal studies to decrease the number of senescent bone marrow stromal cells and preosteoblasts and to increase the osteogenic capacity. Neutralizing antibodies can also inhibit senescence by targeting specific SASP components, such as TNF-α, TGF-β, IL-1β, IL-6, and IL-8. These drugs effectively ameliorate bone loss in inflammation-related diseases. Unfortunately, the efficiency of these anti-SASP agents in clinical OP is obscure.
Herpes Simplex Infection Doubles the Later Risk of Dementia
https://www.fightaging.org/archives/2024/02/herpes-simplex-infection-doubles-the-later-risk-of-dementia/
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.
Increased Dietary Leucine Activates mTOR Signaling in Macrophages, Accelerating Atherosclerosis
https://www.fightaging.org/archives/2024/02/increased-dietary-leucine-activates-mtor-signaling-in-macrophages-accelerating-atherosclerosis/
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.
Repeated Cycles of a Fasting-Mimicking Diet Reduce Measures of Biological Age
https://www.fightaging.org/archives/2024/02/repeated-cycles-of-a-fasting-mimicking-diet-reduce-measures-of-biological-age/
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.
The Gut Microbiome and Alzheimer’s Disease
https://www.fightaging.org/archives/2024/02/the-gut-microbiome-and-alzheimers-disease/
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.
MDM2 Inhibition Reduces Loss of Synapses in a Cell Culture Model
https://www.fightaging.org/archives/2024/02/mdm2-inhibition-reduces-loss-of-synapses-in-a-cell-culture-model/
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.”
Aged Pancreatic Fibroblasts Secrete GDF-15, Encouraging Tumor Growth
https://www.fightaging.org/archives/2024/02/aged-pancreatic-fibroblasts-secrete-gdf-15-encouraging-tumor-growth/
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.
Mitochondrial Uncoupler BAM15 Modestly Extends Life in Flies
https://www.fightaging.org/archives/2024/02/mitochondrial-uncoupler-bam15-modestly-extends-life-in-flies/
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.
Particulate Air Pollution Correlates with Risk of Alzheimer’s Disease
https://www.fightaging.org/archives/2024/02/particulate-air-pollution-correlates-with-risk-of-alzheimers-disease/
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.
Early Life Physical Fitness Correlates with Lesser Degrees of Atherosclerosis in Later Life
https://www.fightaging.org/archives/2024/03/early-life-physical-fitness-correlates-with-lesser-degrees-of-atherosclerosis-in-later-life/
Lifestyle choices related to physical fitness have an impact on many aspects of degenerative aging. As noted here, the pace at which atherosclerosis develops is one of these aspects. Atherosclerosis is the buildup of fatty deposits in blood vessel wall tissue. Those deposits grow into atheromas that ultimately rupture to produce stroke and heart attack. It is the largest single cause of human mortality. Atherosclerosis is a dysfunction of cholesterol transport and the innate immune cells known as macrophages that are responsible for clearing excess cholesterol from blood vessel walls. Over a full lifetime of exposure, lifestyle choice that affect level of inflammation, immune function, and amount of cholesterol in the bloodstream can adjust the risk of later atherosclerosis. Choosing to maintain physical fitness is influential when maintained over decades.
It is well-known that being physically unfit at a young age is linked to an increased risk of cardiovascular disease much later in life. In the study, the researchers linked information from the Swedish Military Conscription Register to SCAPIS (the Swedish Cardiopulmonary Bioimage Study), a large population study on heart and lung health in individuals aged 50 to 64 years. For almost 9,000 men who participated in SCAPIS, data on them at conscription at age 18 from 1972 to 1987 were also available. One of the strengths of the study is that it is based on the general population and that the men have been followed for a long time, an average of 38 years.
The researchers examined the coronary arteries, which supply blood to the heart muscle, using coronary CT angiography, CCTA. The study is the first to use this state-of-the-art technology to examine plaques in the coronary arteries in relation to physical fitness at a young age. In addition, the researchers studied two different types of plaques in the coronary arteries. Plaques with calcium deposits are easy to measure and have long been the focus. “We see in our study that both good cardiorespiratory fitness and good muscle strength in youth are associated with a lower risk of atherosclerosis in the coronary arteries almost 40 years later.”
Assessing Epigenetic Age Acceleration as a Predictor of Age-Related Morbidity and Mortality
https://www.fightaging.org/archives/2024/03/assessing-epigenetic-age-acceleration-as-a-predictor-of-age-related-morbidity-and-mortality/
Researchers here report on an assessment of epigenetic clocks (and PhenoAge). The study is one of a fair number of attempts to quantify just how effective these aging clocks are when it comes to predicting age-related disease and death. The interesting conclusion here is that epigenetic age acceleration, as determined using the present leading epigenetic clocks, isn’t yet a meaningful improvement over the established, traditional, very low-tech correlations with age-related disease and death, such as socioeconomic status. This suggests that we should expect some years of further evolution of aging clocks of various forms before they become truly useful. That evolution will certainly take place: clocks are not going away, are a popular area of research and development, and significant effort is being devoted to their improvement.
Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from 3,581 Health and Retirement Study (HRS) participants to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality.
We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, socioeconomic status (SES), and health behaviors.
In our sample, age acceleration calculated using “second and third generation clocks,” PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 years after DNAm measurement, and 4-year mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.
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