Fight Aging! Newsletter, March 18th 2024

Can you explain the concept of "longevity escape velocity" and its significance in the pursuit of extending human lifespan? When do you think we will reach longevity escape velocity?

LEV is defined as the minimum rate at which medicines need to be improved in order that people receiving the latest medicines can avoid age-related chronic conditions indefinitely. The reason why that rate is finite is that these medicines will be ones that reduce biological age, rather than just slowing the rate at which biological age rises - in other words, each incremental advance will buy time to develop the next one. LEV becomes initially achievable when we have medicines that postpone aging by around 20 years, and I currently think we have a 50% chance of reaching that point within about 12-15 years from now.

Do you see anything being commercially available for longevity/treating aging in the next 5-10 years?

Yes and no. Because aging is not one process but a bunch of only loosely communicating processes, we will address some parts of it sooner than others. So at this point, treatments for some of the easier parts are already in clinical trials and will very probably hit the streets in only a couple of years. But it will probably take a decade longer for enough of the parts of aging to be addressed that we see bona fide postponement of all chronic conditions of old age, which is what most people mean by treatments for aging.

Are there any developments (research, startups etc) that have excited you recently? Any potential up and coming therapies that you find interesting/think more people should know about?

Of course! The field is exploding right now. I'll just pick one: THIO, which is a new anti-cancer drug that kills cells which are making large amounts of telomerase, which means 90% of all human cancers and basically no non-cancer cells. It's in a phase 2 clinical trial being run by MAIA Biotechnology.

In 1953, aged 27, Paul Janssen set up the research laboratory on the third floor of his parents' Belgian drug import firm from where he would grow his eponymous pharmaceutical company. In the years between the 50s and 90s when he was most active, Janssen and his team developed over 70 new medicines, many of which are still in use today. Such prolificacy is unlikely to be repeated any time soon; if current trends hold, a drug discovery scientist starting their career today is likely to retire without ever having worked on a single drug that makes it to market.

The cost to discover and develop a drug today is orders of magnitude higher than in the 1950s. Despite this, the probability that a drug entering clinical trials will eventually reach the market has hardly improved in the intervening years. If Janssen were born today, there's little chance he would be able to repeat his success. He would probably not even get the chance to start.

What changed? Some lay the blame for these deteriorating conditions on regulators like the FDA, claiming that if we were to abolish regulators we would release the stranglehold on industry and unleash a deluge of stalled medicines. Others blame 'big pharma', claiming the industry is suppressing cures - more interested in price gouging on old drugs than investing in R&D. These explanations lack nuance. In reality, the productivity crisis in the pharmaceutical industry is the culmination of decades of just about every aspect of drug discovery and development getting gradually harder and more expensive.

So how did one man and his start-up manage to achieve a level of output that would be the envy of today's pharmaceutical giants?

The hippocampus, a medial temporal lobe structure that is a critical substrate (i.e., central nervous system component) that underlies learning and memory functions, can be adversely affected by a wide range of pathogens, neurotoxins, diseases, injuries, and environmental insults. It has often been suggested that the harmful effects of these insults may be greater on the hippocampus compared to other brain areas. However, there has been no systematic examination of this claim. An important reason to conduct this examination is that Alzheimer's disease and the severe dementia it causes are characterized by extensive hippocampal pathophysiology. It may be that insults that impair hippocampal functioning earlier in life may accelerate the emergence of more extensive hippocampal pathologies that could increase the risk of serious late-life cognitive decline.

One purpose of this review is to assess the vulnerability of the hippocampus to the most prevalent types of insults in multiple biomedical domains (i.e., neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, neurodegenerative disease, acquired brain injury, mental health conditions, endocrine disorders, developmental disabilities, nutrition) and to evaluate whether these insults affect the hippocampus first and more prominently compared to other brain loci. A second purpose is to consider the role of hippocampal blood-brain barrier (BBB) breakdown in either causing or worsening the harmful effects of each insult. Recent research suggests that the hippocampal BBB is more fragile compared to other brain areas and may also be more prone to the disruption of the transport mechanisms that act to maintain the internal milieu. Moreover, a compromised BBB could be a factor that is common to many different types of insults.

Our analysis indicates that the hippocampus is more vulnerable to insults compared to other parts of the brain. Our findings also indicate that hippocampal vulnerability to many of these insults is accompanied by a loss of BBB integrity in this region. For some of these insults, there was evidence that weakening of the hippocampal BBB occurred before and was more pronounced compared to the BBBs of other brain areas. These conclusions are limited, especially when considering the hippocampal BBB, by a lack of relevant data or by equivocal findings, with respect to the effects of some insults. In addition to the need to more rigorously test the notion of unique hippocampal vulnerability, we conclude that addressing the questions of how the protections afforded by the hippocampal BBB are compromised and how that weakening impairs hippocampal functioning are research goals of major significance, given the wide range of insults to which the hippocampus is vulnerable.

Epigenetic biomarkers of aging (aging clocks) can predict biological age through a variety of training approaches, even when based only on the variance of DNA methylation during aging. Interestingly, reacquisition of the lost epigenetic information may be observed during the natural rejuvenation process that occurs during early embryogenesis as well as during cell reprogramming. These strategies are in line with the notion of reprogramming-induced rejuvenation (RIR), a recent discovery wherein old cells can revert to a younger state upon transcription factor or chemical treatments. RIR is commonly accomplished through partial cell reprogramming, a method in which cells transiently undergo an induced pluripotent stem cell (iPSC) reprogramming. In this perspective, we discuss recent advances in this area, offer insights how they are related to the nature of aging and rejuvenation, and highlight potential advantages and drawbacks of this RIR and its translational potential.

It was shown that partial cell reprogramming can enhance the physiological function of human muscle stem cells, ameliorate the aging mouse transcriptome and metabolome in vivo, rejuvenate human dermal fibroblasts on a multi-omics level, and reverse the epigenetic clock in vitro. Furthermore, partial reprogramming can restore visual function in mice, prevent age-related physiological changes, and extend the remaining lifespan in wild-type mice. Present evidence suggests that pluripotency is not inherently linked to the rejuvenation process. However, it remains unclear whether pluripotency or certain transitionary cell states can be completely uncoupled from rejuvenation. A key question to be investigated is whether certain components contributing to biological age reversal can rejuvenate the entire epigenome or only certain loci.

There are legitimate concerns about the safety of Yamanaka factor-mediated partial reprogramming. To translate research in the field into clinical therapies, more research on the roadmap of partial reprogramming needs to be conducted. Furthermore, to better evaluate the results of in vivo cyclic reprogramming studies, in vitro cyclic reprogramming must be performed, and the difference between cyclic and continuous partial reprogramming must be identified. In conclusion, while partial reprogramming holds great therapeutic potential, the real focus should be on rejuvenation research, defining its nature and ways to quantify it. Another critical issue is the ability to quantify biological age as reprogrammed older cells acquire younger states. Understanding rejuvenation is also key to translational success, as benefits of age reversal must be considered against risks. More research into safety and tissue-specific responses of this technique are required.

This article summarizes research presented at the virtual symposium and workshop, "New Approaches for Understanding the Potential Role of Microbes in Alzheimer's Disease." The objective of these events was to review the evidence base and catalyze research to address knowledge gaps in the hypothesis that infections or microbes play some causative role in the development or progression of Alzheimer's disease. Alzheimer's disease is a complex disease; this symposium was rooted in an understanding that its pathogenesis could be triggered by both microbe-dependent and microbe-independent pathways and the two are not mutually exclusive.

The symposium was introduced with a keynote lecture describing the origins and accumulating evidence for the theory around amyloid-β (Aβ) as an antimicrobial protein that protects the brain against infection. The next session highlighted epidemiological and mechanistic data for a potential link between COVID-19 and Alzheimer's disease. The program then featured brief lectures that explored these topics: single-cell genomic studies in Alzheimer's disease that may suggest immune response to microbes, a potential role for antiviral vaccines in Alzheimer's disease, investigations into which microbes could cause Alzheimer's, activation of endogenous retroviruses in tauopathy, and gut-microbe brain communications.

Speakers presented emerging evidence that COVID-19 infection confers increased risk of dementia and discussed how COVID-19 may promote AD pathology. Although no definitive evidence exists to prove or disprove the direct involvement of any specific microbe in human AD, speakers agreed that there are multiple plausible ways that microbes could be implicated. One model that has been extensively investigated that has direct relevance to central nervous system (CNS)/microbiome interactions are the effects of lipopolysaccharide (LPS) on blood-brain barrier (BBB) functions. LPS is derived from gram negative bacteria and is a powerful activator of the innate immune system. LPS's actions either directly on BBB functions or indirectly through the induction of the release of cytokines and other immune-related substances affect the CNS.

Data also shows that some microbes appear to be overabundant in Alzheimer's brains, sometimes by large margins. These microbes are species typically encountered in human infections - for example, Streptococcus and Staphylococcus, as well as several Aspergillus-like, Candida-like, and Cryptococcus-like fungi, of interest because Cryptococcus in particular is a known cause of dementia 'masquerading' as Alzheimer's disease. Infections appeared to be locally restricted - some samples with a heavy microbial burden were adjacent to tissues largely lacking microbes. Conversely, some atypical microbes were seen in more than one brain region, indicative of in vivo spreading. However, whether microbes cause Alzheimer's remains an open question. One way to evaluate this would be to determine which brain microbes are present in each individual (perhaps through analysis of cerebrospinal fluid), and then to explore whether appropriate therapy might mitigate or slow Alzheimer's disease.

To measure the pace of aging, the researchers applied an algorithm known as the DunedinPACE epigenetic clock to genomic data collected by the Framingham Heart Study. The latest findings showed that, according to the yardstick of the DunedinPACE epigenetic clock, two years of additional schooling translated to a 2-3% slower pace of aging. This slowing in the pace of aging corresponds to a roughly 10 percent reduction in risk of mortality in the Framingham Heart Study, according to previous research on the association of DunedinPACE with risk of death.

The researchers used data from 14,106 Framingham Heart Study spanning three generations to link children's educational attainment data with that of their parents. They then used data from a subset of participants who provided blood samples during data collection to calculate the pace of biological aging using the DunedinPACE epigenetic clock. In primary analysis, the researchers tested associations between educational mobility, aging, and mortality in a subset of 3,101 participants for whom educational mobility and pace of aging measures could be calculated. For 2,437 participants with a sibling, the researchers also tested whether differences in educational attainment between siblings were associated with a difference in the pace of aging.

"A key confounder in studies like these is that people with different levels of education tend to come from families with different educational backgrounds and different levels of other resources. To address these confounds, we focused on educational mobility, how much more (or less) education a person completed relative to their parents, and sibling differences in educational attainment - how much more (or less) education a person completed relative to their siblings. These study designs control for differences between families and allow us to isolate the effects of education."

By combining these study designs with the new DunedinPACE epigenetic clock, the researchers were able to test how education affects the pace of aging. Then, by linking the education and pace of aging data with longitudinal records of how long participants lived, the team was able to determine if a slower pace of aging accounted for increased longevity in people with more education. "We found that upward educational mobility was associated both with a slower pace of aging and decreased risk of death. In fact, up to half of the educational gradient in mortality we observed was explained by healthier aging trajectories among better-educated participants." This pattern of association was similar across generations and held within family sibling comparisons: siblings with higher educational mobility tended to have a slower pace of aging as compared with their less educated siblings.

The search for interventions to slow down and even reverse aging is a burgeoning field. The literature cites hundreds of supposedly beneficial pharmacological and genetic interventions in model organisms: mice, rats, flies and worms, where research into physiology is routinely accompanied by lifespan data. However, when experimental animals from one article live as long as controls from another article, comparing the results of interventions across studies can yield misleading outcomes. Theoretically, all lifespan data are ripe for re-analysis: we could contrast the molecular targets and pathways across studies and help focus the further search for interventions. Alas, the results of most longevity studies are difficult to compare.

This is in part because there are no clear, universally accepted standards for conducting such experiments or even for reporting such data. The situation is worsened by the fact that the authors often do not describe experimental conditions completely. As a result, works on longevity make up a set of precedents, each of which might be interesting in its own right, yet incoherent and incomparable at least for the reason that in a general context, it may indicate, for example, not prolonging the life of an average organism, but compensating for any genetic abnormalities of a particular sample or inappropriate living conditions. Here we point out specific issues and propose solutions for quality control by checking both inter- and intra-study consistency of lifespan data.

"Reconstructive surgery to correct trauma to the face or head from injury or disease is usually imperfect, resulting in scarring or permanent hair loss. With this work, we demonstrate bioprinted, full thickness skin with the potential to grow hair in rats. That's a step closer to being able to achieve more natural-looking and aesthetically pleasing head and face reconstruction in humans." While scientists have previously 3D bioprinted thin layers of skin, this team is the first to intraoperatively print a full, living system of multiple skin layers, including the bottom-most layer or hypodermis. Intraoperatively refers to the ability to print the tissue during surgery, meaning the approach may be used to more immediately and seamlessly repair damaged skin. The top layer - the epidermis that serves as visible skin - forms with support from the middle layer on its own, so it doesn't require printing.

The hypodermis, made of connective tissue and fat, provides structure and support over the skull. "The hypodermis is directly involved in the process by which stem cells become fat. This process is critical to several vital processes, including wound-healing. It also has a role in hair follicle cycling, specifically in facilitating hair growth."

The researchers started with human adipose, or fat, tissue obtained from patients undergoing surgery. The team extracted the extracellular matrix - the network of molecules and proteins that provides structure and stability to the tissue - to make one component of the bioink. The team also obtained stem cells, which have the potential to mature into several different cell types if provided the correct environment, from the adipose tissue to make another bioink component. Each component was loaded into one of three compartments in the bioprinter. The third compartment was filled with a clotting solution that helps the other components properly bind onto the injured site. "The three compartments allow us to co-print the matrix-fibrinogen mixture along with the stem cells with precise control. We printed directly into the injury site with the target of forming the hypodermis, which helps with wound healing, hair follicle generation, temperature regulation, and more."

Studies suggest that inducing gut microbiota changes may alter both muscle physiology and cognitive behaviour. Gut microbiota may play a role in both anabolic resistance of older muscle, and cognition. In this placebo controlled double blinded randomised controlled trial of 36 twin pairs (72 individuals), aged ≥60, each twin pair are block randomised to receive either placebo or prebiotic daily for 12 weeks. Resistance exercise and branched chain amino acid (BCAA) supplementation is prescribed to all participants. Outcomes are physical function and cognition. The trial is carried out remotely using video visits, online questionnaires and cognitive testing, and posting of equipment and biological samples.

The prebiotic supplement is well tolerated and results in a changed gut microbiome, e.g. increased relative Bifidobacterium abundance. There is no significant difference between prebiotic and placebo for the primary outcome of chair rise time (β = 0.579). The prebiotic improves cognition (factor score versus placebo (β = -0.482). Our results demonstrate that cheap and readily available gut microbiome interventions may improve cognition in our ageing population. We illustrate the feasibility of remotely delivered trials for older people, which could reduce under-representation of older people in clinical trials.

The TRPV2 ion channel is formed by proteins in the membrane of some cells. When activated, they allow the entry of positive ions from the extracellular environment, changing the state of the cell and temporarily modifying aspects such as its ability to replicate, contract (in the case of a muscle cell) or even causing its death.

In a first study, the mechanisms involved in the contraction and relaxation of blood vessels by TRPV2 activation were analyzed in male mice. The researchers saw that TRPV2 produces multiple effects in different layers of the blood vessel, resulting in vasodilation. "This is important because it is the first time that the processes triggered by the activation of TRPV2 in blood vessels have been identified and have been described as leading to their dilation. This study represents a very important starting point for using this TRPV2 activation as a therapeutic strategy against diseases that cause excessive vasoconstriction, such as hypertension."

In a second study, the research group used computational techniques to identify a set of 270 molecules that, due to their physical and chemical characteristics, could interact with TRPV2, and grouped them by families according to how each of these molecules would bind to TRPV2. Then, by expressing the TRPV2 protein in yeast, a screening system was designed to test its effects. This made it possible to find a molecule (4-piperidin-1-sulfonyl-benzoic acid) capable of activating this protein more powerfully than the only drug known so far to do so: probenecid. "The activation of TRPV2 produced by the new molecule identified in this study has a very interesting vasodilator effect that could be used in the future as an antihypertensive therapy."

Rejuvenate Biomed, a pioneering clinical-stage platform and pipeline company committed to enhancing lifelong health through innovative therapeutics, today announces breakthrough functional outcome results from its Phase 1b trial of lead candidate RJx-01 for the treatment of sarcopenia. RJx-01 is a proprietary combination of metformin and galantamine that was identified by the company's in-house drug discovery platform and has shown to have beneficial effects on various preclinical models of sarcopenia. The recent exploratory clinical trial results, which follow earlier confirmation of safety, tolerability, and pharmacokinetics, highlight the potential of RJx-01 in addressing the unmet need for effective sarcopenia treatments.

Participants with disuse-induced sarcopenia treated with RJx-01 exhibited a promising improvement in muscle strength recovery compared to the placebo group. This beneficial effect, assessed through isometric dynamometry, underscores the ability of RJx-01 to promote muscle strength improvement. Treatment with RJx-01 led to an important improvement of leg acceleration, assessed through isokinetic dynamometry. The ability to accelerate the limb rapidly is important for functional movement in daily activities and is pivotal in mitigating fall risks. Neuromuscular fatigue was assessed by monitoring muscle parameters during a series of leg exercises. Participants receiving RJx-01 showed a reduced propensity for fatigue indicating that RJx-01 can promote physical activities such as walking.

The transcription factors (genes) Gfi1, Atoh1, Pou4f3, and Six1 (known collectively as GAPS) are important for the development and survival of hair cells. Previous research trying to regenerate hair cells in mature damaged ears by using a single transcription factor, Atoh1, produced very few cells. It also failed to produce new hair cells in severely injured organs of Corti, especially those with flat epithelium, a condition where sensory hair cells and supporting cells in the cochlea are lost and the organ of Corti turns into a simple flat layer of cells.

Studies in vitro suggested using combinations of transcription factors could be more effective than any single factor. We looked at the effects of overexpressing the GAPS genes in the ears of mature guinea pigs that were deafened and had flat epithelium. Seven days after deafening, adenovirus vectors carrying GAPS were injected into the inner ear scala media (cochlear duct) and successfully expressed in the flat epithelium. One or two months later, we observed cells expressing the protein Myosin VIIa, which marks hair cells. Surprisingly, most of these cells were in regions under the flat epithelium, not within it. Two months after treatment, we saw that some GAPS-treated guinea pigs had a statistically significant increase in new hair cell-like cells compared with controls.

In summary, our results showed that overexpression of GAPS enhances the potential for generating new hair cell-like cells in a severe inner ear lesion model characterized by flat epithelium in the guinea pig, compared with using Atoh1 alone. The new hair cells need to connect with nerve fibers to potentially restore hearing. We saw some promising signs of nerve regrowth, but more research is needed to determine if the new cells can signal to auditory nerves, even in their unusual location.

Colon cancer usually arises in long-lived cells called intestinal stem cells, whose job is to continually regenerate the lining of the intestines. To learn more about how these precancerous growths evade the immune system, the researchers used a technique they had previously developed for growing mini colon tumors in a lab dish and then implanting them into mice. In this case, the researchers engineered the tumors to express mutated versions of cancer-linked genes Kras, p53, and APC, which are often found in human colon cancers.

Once these tumors were implanted in mice, the researchers observed a dramatic increase in the tumors' expression of SOX17. This gene encodes a transcription factor that is normally active only during embryonic development, when it helps to control development of the intestines and the formation of blood vessels. The researchers' experiments revealed that when SOX17 is turned on in cancer cells, it helps the cells to create an immunosuppressive environment. Among its effects, SOX17 prevents cells from synthesizing the receptor that normally detects interferon gamma/en.wikipedia.org/wiki/Interferon_gamma">interferon gamma, a molecule that is one of the immune system's primary weapons against cancer cells.

Without those interferon gamma receptors, cancerous and precancerous cells can simply ignore messages from the immune system, which would normally direct them to undergo programmed cell death. Without interferon gamma signaling, cancer cells also minimize their production of molecules called MHC proteins, which are responsible for displaying cancerous antigens to the immune system. The cells' insensitivity to interferon gamma also prevents them from producing immune molecules called chemokines, which normally recruit T cells that would help destroy the cancerous cells.

When the researchers generated colon tumor organoids with SOX17 knocked out, and implanted those into mice, the immune system was able to attack those tumors much more effectively. This suggests that preventing cancer cells from turning off SOX17 could offer a way to treat colon cancer in its earliest stages. As part of their study, the researchers also analyzed gene expression data from patients with colon cancer and found that SOX17 tended to be highly expressed in early-stage colon cancers but dropped off as the tumors became more invasive and metastatic.

Even as obesity treatments Ozempic and Mounjaro continue their surge in popularity, drug hunters are asking whether it is possible for people to lose weight on these glucagon-like peptide-1 (GLP-1) agonists without losing muscle. Drug candidates originally designed to build, preserve or regenerate skeletal muscle for treating muscle atrophy in degenerative conditions or ageing are now being tested in combination with GLP-1 agonists used for obesity to spare lean muscle.

One such biotech is BioAge Labs. In February, the company announced a 170-million series D financing, which will allow it to combine its apelin receptor agonist azelaprag (BGE-105) with Eli Lilly's GLP-1 agonist Mounjaro (tirzepatide) in phase 2 studies. The combination preserved lean body tissue in phase 1 studies and animal models and boosted weight loss by 10-15% compared with Mounjaro alone. The news came on the heels of Regeneron's intention to launch a phase 2 trial pairing the company's muscle-preservation monoclonal antibodies (the anti-myostatin trevogrumab and the anti-activin A garetosmab) alongside Novo Nordisk's Ozempic (semaglutide).

Immunis and Juvena Therapeutics are zooming in on the muscle stem cell secretome - the collection of proteins, including growth factors, cytokines, chemokines, and extracellular matrix components, secreted by muscle cells. The secretome kicks in to boost proliferation in response to exercise or to enhance cellular interactions to accelerate wound healing, for example, and it declines markedly with age. For Paris-based Biophytis, the focus is on the shared pathways between age-related sarcopenia and neuromuscular disease such as Duchenne muscular dystrophy. Its lead candidate is ruvembri (BIO101), a small molecule that targets the MAS receptor, which is present in cardiorespiratory and skeletal muscles. MAS activates the AKT and AMPK kinase pathways downstream, stimulating protein synthesis and energy production, respectively.

Companies with muscle-building drugs are now blazing a trail in obesity studies to counter the skeletal muscle atrophy that accompanies fat-loss treatments. The often dramatic weight loss experienced by people who have undergone bariatric surgery or are taking GLP-1 agonists such as Mounjaro and Ozempic leads to the loss of muscle as well as fat. As a consequence, biopharma companies are on the lookout for drugs to use alongside GLP-1 agonists to preserve lean muscle mass.

Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating cell fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron - particularly during mitosis.

To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.