Yet More Development of Proteomic Signatures of Longevity

The cost of obtaining transcriptomic and proteomic data, and then using machine learning techniques to develop insights based on that data, has fallen dramatically over the past decade. As a result there is a proliferation of signatures of aging and longevity, as many different research groups analyze many different large transcriptomic and proteomic databases. The example here is one of a number of such signatures created with the idea of finding potential targets for therapy. It is far from clear that one can alter any of the various protein levels related to aging and longevity and obtain meaningful benefits, however. A change can be a side-effect of aging, and end-stage consequence that causes few downstream consequences in and of itself, and will achieve little if reversed.

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3,067 participants from the Cardiovascular Health Study (CHS) and 4,690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the AGES-Reykjavik replication cohort and 105 were replicated.

The strongest associations in CHS that were replicated in AGES-Reykjavik were for GDF-15, NT-pro-BNP, b2-microglobulin, RNase 1, and HE4, providing confidence in such previously identified proteins in aging research. Less-established markers of mortality in the general population, such as angiopoietin-2, and PXDN, also had support in both cohorts. Our study design leveraging a longevity outcome, as opposed to overall survival only, paired with long follow-up time revealed that nearly half (269 out of 471) of proteins associated with overall survival were not associated with exceptional longevity in the CHS, though the strongest associations remained consistent between the two outcomes.

A larger share of significant proteins was associated with both overall survival and longevity in AGES-Reykjavik, which may have occurred due to increased power to detect significant associations in AGES-Reykjavik. This observation suggests that extrapolating findings from associations with overall survival to longevity might be inappropriate. Moreover, we demonstrate for the first time in proteomics studies of longevity that physical and cognitive function may partially mediate associations between proteins and longevity, and that the amount of mediation may depend in part on which particular functional measures are used in the analysis.

Link: https://doi.org/10.1111/acel.14136

Aspects of Skin Aging Encourage Metastasis in Melanoma

There are many ways in which the aging of tissue makes cancer both more likely to occur and more aggressive once it does occur. Here researchers focus in on specific changes in aged skin tissue that make melanoma cancers more likely to become metastatic and spread to other organs. Interestingly, it is an indirect effect on cell signaling that is mediated by increased stiffness of the skin extracellular matrix, an issue in many aging tissues that has many root causes, not just the one noted here. Nonetheless, if metastasis could be shut down, then cancer would become a much more tractable problem, particularly if control of metastasis were to be combined with improved approaches to the early detection of cancer.

Previous research has shown that a protein called HAPLN1 helps maintain the structure of the extracellular matrix, a network of molecules and minerals that provide structural support, to keep the skin supple. As people age, they release less HAPLN1, which causes the skin to stiffen. A new study shows that reduced HAPLN1 indirectly increases ICAM1 levels by causing stiffening, which alters cellular signaling. The increase in ICAM1 contributes to angiogenesis, or the growth of new blood vessels that supply the tumors with nutrients and help them grow. The blood vessels are also leakier, making it easier for tumor cells to escape from the initial tumor site and spread to distant areas of the body.

Treating older mice with melanoma with drugs that block ICAM1, however, prevents these changes, shrinking their tumors and reducing metastasis, researchers demonstrated. The researchers are now studying ICAM1's activities to develop more precise ways of targeting it with drugs, which might lead to new approaches to treating older people with melanoma. The discoveries might also lead to new approaches to treating other age-related cancers. Previous therapies targeting growth factors that contribute to angiogenesis have failed in many tumor types, including melanoma. But ICAM1 provides a promising new target.

Link: https://www.eurekalert.org/news-releases/1037180

Reporting on a Nine Month Self-Experiment in Taurine Supplementation

Today's post is a report from the community on the impact of taurine supplementation on a few biomarkers of interest. Taurine is a dietary amino acid, and circulating levels of taurine influence any number of biological processes. Taurine levels decrease with age in a variety of species; in humans circulating taurine is halved by age 50. You might recall that supplementation with taurine was demonstrated to modestly extend life in mice and improve health in old non-human primates. This may be largely due to enhanced performance of the antioxidant glutathione, and you might recall that other approaches to upregulation of glutathione activity have been shown to produce benefits in old humans, dampening oxidative stress and associated inflammation.

A few human clinical trials of taurine supplementation have been conducted, but the results are not all that conclusive, other than to demonstrate that this form of intervention is very safe. So why not give it a try, and see what results? If you look back in the Fight Aging! archives, you'll find an outline for a self-experiment with taurine supplementation. Taurine is cheap and readily available as as a supplement, and inexpensive blood tests can be used to assess outcomes. Here, the self-experimenter chose to focus on phenotypic age and the biomarkers used to construct this assessment of phenotypic age. Only one marker of oxidative stress was used, an assessment of circulating oxidized LDL particles.

  • The self-experimenter was a vegetarian in his 50s.
  • 3 grams per day of taurine was taken orally for 9 months.
  • Diet and lifestyle was kept consistent, as much as possible in a busy life.
  • Phenotypic age acceleration: -9.00 to -10.85 years
  • Albumin: 4.1 to 4.3 g/dL (reference range is 3.6-5.1 g/dL)
  • Creatine: 0.72 to 0.65 mg/dL (desired range is 0.70-1.30 mg/dL)
  • Fasting Glucose: 93 to 90 mg/dL (desired range: 65-99 mg/dL)
  • C-Reactive Protein: 0.30 to 0.34 mg/L (considered low risk under 1.00 mg/L)
  • Alkaline Phosphatase (ALP) 53 to 50 U/L (reference range is 35-144 U/L)
  • Lymphocyte Percentage 33.1% to 40.7% (normal range is 20% to 40%)
  • Mean Cell Volume (MCV): 87.8 to 88.6 fL (desired range is 80.0-100.0 fL)
  • Red Cell Dist Width (RDW): 13.3% to 13.5% (desired range is 11.0-15.0%)
  • White Blood Cells (WBC): 4.8 to 3.9 Thousand/uL (reference range is 3.8-10.8 Thousand/uL)
  • Taurine: 43.6 to 114.9 umol/L (reference range is 29.2-132.3 umol/L)
  • Oxidized LDL: 105 to 82 ng/mL (reference range is 10-170 ng/mL)
  • LDL and HDL cholesterol levels were largely unchanged.
  • Absolute Lymphocytes: 1589 to 1587 cells/uL (desired range is 850-3900 cells/uL)
  • Absolute Monocytes: 312 to 269 cells/uL (desired range is 200-950 cells/uL)
  • Absolute Neutrophils: 2832 to 1981 cells/uL (desired range is 1500-7800 cells/uL)
  • Lymphocyte: Monocyte Ratio: 5.1 to 5.9
  • Other complete blood count statistics were largely unchanged.

Going from the data provided, the supplementation successfully increased a low circulating taurine level to a high circulating taurine level as intended, and modestly reduced phenotypic age. The most interesting change seen in the biomarkers making up the phenotypic age metric is the increased lymphocyte percentage. This change was entirely due to the absolute neutrophil count decreasing from 2832 to 1981 cells/uL, while other absolute counts for white blood cell types remained much the same. Neutrophil counts can be raised temporarily by transient infection or inflammation, but per the self-experimenter, ~2800 had been a fairly consistent level for absolute neutrophil count for some years prior to this self-experiment. The observed reduction is thus a novel change, and likely due to the taurine supplementation.

A second interesting point is the reduction in oxidized LDL, a marker of oxidative stress and also a contributing factor in the development of atherosclerosis. As a sidebar, also note the low creatine levels, characteristic of vegetarians since dietary creatine is mostly found in meat.

The modestly favorable results shown here form only a single data point and should be taken as an anecdote, of course. It would be interesting to see the results of a few hundred participant clinical trial of taurine supplementation that focused on the various modern approaches to measuring biological age, such as epigenetic clocks. One shouldn't expect there to be a rush to do this, however. Trials are expensive, and there is little spare funding to be found in the business of selling well-established supplement compounds. At the end of the day modest effect sizes are modest effect sizes, and we'd like to focus on better approaches to the problem of aging - but if the intervention is both very cheap and very safe, then it may well be worth the effort to further establish the degree to which it can be useful.

Interesting Insight into the Relationship Between TP53, Telomerase, and Telomere Length

Telomeres are repeated sequences at the end of chromosomes. A little of that length is lost with each cell division, and in this way telomere length acts as a countdown. Somatic cells become senescent or self-destruct when telomere length becomes too short, thanks in large part to the activity of TP53. This is a protective mechanism, removing cells that can become cancerous or otherwise harmful. Stem cells employ telomerase to maintain long telomeres, and supply a tissue with new daughter somatic cells to take the place of those lost to telomere shortening. Thus a tissue has some turnover of cells, allowing a degree of protection from the most harmful cell malfunctions. This study provides some insight into how these relationships play out in practice by sabotaging telomerase and p53, and observing the results.

Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 which leads to apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic aging. Similarly, zebrafish have restricted telomerase expression, and telomeres shorten to critical length during their lifespan.

Telomerase-deficient zebrafish (tert -/-) is a model of premature aging that anticipates aging phenotypes due to early telomere shortening. tert -/- zebrafish have impaired cell proliferation, accumulation of DNA damage markers and p53 response. These cellular defects lead to disruption of tissue homeostasis, resulting in premature infertility, gastrointestinal atrophy, sarcopenia, and kyphosis. Such consequences contribute to its premature death.

Here we reveal a genetic interdependence between tp53 and telomerase function. Mutation of tp53 abrogates premature aging of tert -/- zebrafish, prolonging male fertility and lifespan. However, it does not fully rescue healthspan. tp53mut tert -/- zebrafish retain high levels of inflammation and increased spontaneous cancer incidence. Conversely, loss of telomerase prolongs the lifespan of tp53mut single mutants. Lack of telomerase reduces two-fold the cancer incidence in double mutants and increases lifetime survival. Thus, we observe a reciprocal rescue of tp53mut and tert -/- that ameliorates lifespan but not spontaneous cancer incidence of tp53mut, likely due to higher levels of inflammation.

Link: https://doi.org/10.1038/s41598-024-56153-8

Calorie Restriction Induces Plasminogen Production to Protect Muscle Tissue

Researchers here identify a mechanism by which the practice of calorie restriction promotes muscle stem cell function, and thus repair and maintenance of muscle tissue. In animal studies calorie restriction is shown to produce both (a) a short-term effect associated with improved regeneration, and (b) a long-term effect in the sense of slowing the progressive loss of muscle mass and strength leading to sarcopenia. The research community will no doubt build on the findings here to suggest pharmaceutical approaches to mimic this aspect of calorie restriction.

Using an unbiased proteomics approach, we report here that calorie restriction (CR) promotes a hypersecretion of proteins from the liver, including those involved in coagulation and fibrinolysis. We also demonstrated the role of liver-derived plasminogen in mediating satellite cell expansion and enhanced muscle regeneration during CR. We showed that the mediation was accomplished by an upregulation of the plasminogen receptor Plg-RKT specifically on muscle satellite cells, promoting downstream ERK signaling and subsequent proliferation. We therefore propose that CR induces a distinct crosstalk between liver and muscle that increases muscle resilience.

Using the MetRSL274G/bio-orthogonal non-canonical amino acid tagging (BONCAT) model to characterize an organ-specific secretome in vivo, our study aimed to investigate the systemic and extracellular effects of CR and how this could alter tissue resilience. We chose to investigate metabolic tissues with known effects of CR, including liver, skeletal muscle, and adipose tissue. We were intrigued by the induction of secreted proteins from the liver with CR, which was not evident in proteins secreted by either adipose or muscle tissues. The induction of the secretome was observed just 2 weeks after CR and continued throughout the 3-month CR period.

Interestingly, CR increased secretion of proteins associated with the resolution of both coagulation and hemostasis. Although not the focus of this paper, these findings suggest increased secretion of fibrinolytic factors from the liver as a possible mechanism to improve cardiovascular health with CR, given that elevated hemostatic factor levels are typically associated with worsened clinical cardiovascular outcomes, such as increased risk of cardiovascular death. Conversely, CR dampened secretion of proteins associated with increased inflammation, which is consistent with known anti-inflammatory effects of CR and further validates our proteomics approach.

To demonstrate the relevance of our findings to human biology, we analyzed tissues from the CALERIE trial of human CR. We observed replication of many of the mouse phenotypes, including increased circulating plasminogen, decreased PAI-1, satellite cell expansion, and increased Plg-RKT expression on the satellite cells of human CALERIE study participants. This study also reports the expansion of satellite cells in human muscle with CR. This finding is critical to suggest translational relevance to the rodent data observed for more than a decade. Moreover, the increased expression of the plasminogen receptor Plg-RKT observed on human satellite cells during CR provided additional support for the theory that our rodent model is relevant to human biology.

Link: https://doi.org/10.1016/j.celrep.2024.113881

Towards a Better Understanding of the Role of the Gut Microbiome in Alzheimer's Disease

The balance of microbial populations making up the gut microbiome changes with age in ways that provoke chronic inflammation, as well as reduce production of beneficial metabolites. In recent years, researchers have shown that Alzheimer's patients exhibit a distinctly dysregulated gut microbiome in comparison to other older individuals. This raises the question of whether there is a significant contribution to risk of Alzheimer's resulting from specific changes in microbial populations of the intestinal tract. Alternatively, since the immune system is responsible for gardening the gut microbiome, eliminating undesirable microbes, does the Alzheimer's gut microbiome reflect a specific or greater incapacity of the immune system that independently drives both changes in the gut microbiome and the development of neurodegeneration?

In today's open access paper, researchers discuss the path towards a better understanding of the role of the gut microbiome in Alzheimer's disease. At present a correlation is established, but how to move beyond that to identify specific mechanisms and microbial populations? One possible approach to the question of causation is to attempt to reverse age-related or disease-related changes in the gut microbiome via fecal microbiota transplant from a young, healthy individual. Finding out whether this improves Alzheimer's patient outcomes, and to what degree, would be an important step forward. If the problem is that microbes make their way from a leaky gut to the brain and there causing issues, changing the gut microbiome may not help in later stages of the condition, however. If the problem is altered inflammatory signaling and metabolite production in the intestines, then changing the microbiome may be more helpful.

New approaches for understanding the potential role of microbes in Alzheimer's disease

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.

Lowered Iron Levels in Hematopoietic Stem Cells Reverse Some Age-Related Dysfunction

Researchers here report on a way to reverse some of the age-related dysfunction observed in the hematopoietic stem cell population resident in bone marrow. These cells are responsible for generating red blood cells and immune cells. Some fraction of the age-related decline in immune function derives from issues in the hematopoietic cell populations originating with hematopoietic stem cells. It seems that hematopoietic stem cells have a distinct iron metabolism, and iron accumulation produces dysregulation in these cells. Reducing the presence of iron in hematopoietic stem cells reverses some of these changes. In the bigger picture, iron is connected to aging, and global reductions in iron levels achieved via a variety of methods have been demonstrated to modestly slow life in short-lived laboratory species such as flies and worms. Just how much of that effect derives from improved hematopoietic and immune function is an open question.

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.

Link: https://doi.org/10.1016/j.stem.2024.01.011

Efforts to Produce Drugs to Slow or Reverse Sarcopenia Benefit from the Semaglutide Hype

This popular science article is a reminder that all too little in this world happens for entirely rational reasons. Drugs aimed at slowing or reversing the age-related loss of muscle mass leading to sarcopenia are presently under development by a number of companies, though none of the candidates discussed are producing effect sizes that look very favorable in comparison to the effects of resistance exercise. These efforts will likely benefit from the present manufactured hype that attends the use of antidiabetic GLP1 receptor agonists for weight loss, as one of the side-effects of this drug is modest loss of muscle mass. To the extent that this aids in the development of meaningful ways to treat sarcopenia, fair enough. But one is left with the lingering feeling that perhaps this is not the best way to make progress. Will these companies continue to work on age-related disease, or will they just get shunted into the non-aging-related hype of the day? The latter is not a small risk.

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.

Link: https://doi.org/10.1038/s41587-024-02176-5

Reviewing the Path Towards Reprogramming as a Basis for Rejuvenation Therapies

Reprogramming using overexpression of the Yamanaka factors captures a portion of the changes that take place in early embryonic development, in the creation of youthful embryonic stem cells from old germline cells. Reprogramming can erase cell state, slowly turning adult somatic cells into what are known as induced pluripotent stem cells, analogous to embryonic stem cells. But researchers have realized that the potentially far more interesting outcome is that prior to transformation, cells shift their epigenetic patterns towards a more youthful configuration. This reverses age-related mitochondrial dysfunction, and likely many other detrimental changes in cell behavior.

Thus the focus of reprogramming in academia and industry is shifting from the production of pluripotent cells for research and cell therapies to the rejuvenation of cells in aged living tissue. Researchers are earnestly seeking therapeutic modalities that can strike the balance between enough exposure to reprogramming factors to produce epigenetic rejuvenation, but not so much as to cause cells in tissue to become pluripotent and cancerous. This partial reprogramming is a challenge, but serious efforts to reach this goal are underway.

It has long seemed that the first rejuvenation therapies to reach the clinic and be demonstrated to slow aging in humans would be forms of senolytic drug capable of selectively clearing senescent cells. Groups working on partial reprogramming appear to be catching up rapidly, however. Efforts to build therapies atop the present understanding of partial reprogramming are now backed by massively greater funding than senolytic research and development. The field is moving rapidly as a consequence. With this as a background, the authors of today's open access review paper cast an eye over the present state of partial reprogramming as a basis for rejuvenation. It is an interesting read.

The long and winding road of reprogramming-induced rejuvenation

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.

SOX17 Allows Early Stage Colon Cancer to Evade the Immune System

Researchers here report on work that identifies SOX17 inhibition as a potential way to attack colon cancer in its early stages. Any successful cancer must have adopted one or more ways to suppress the immune system in order to grow past the earliest stages of a few cancerous cells. Interfering in those suppression mechanisms is a potential basis for therapy, as the researchers demonstrated here. Whether or not this line of work will make much further depends on whether an economically viable approach to SOX17 inhibition can be found, and whether or not it is a good target for many other forms of cancer.

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.

Link: https://news.mit.edu/2024/how-early-stage-cancer-cells-hide-immune-system-0228

Further Progress Towards Regeneration of Sensory Hair Cells to Treat Deafness

In recent years, researchers have attempted to provoke the regeneration of lost sensory hair cells in the inner ear, a potential treatment for forms of deafness. Various genes related to the creation of these cells during development have been identified, and gene therapy interventions attempted in animal models. Progress has been made, but it is incremental, and the results not yet satisfactory. Noted here is a recent example of this sort of work, in which a cocktail of genes is employed rather than focusing on single gene interventions.

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.

Link: https://hearinghealthfoundation.org/blogs/combination-of-four-genes-may-help-regrow-new-auditory-hair-cells-in-mammals

Is the Aging Hippocampus Particularly Vulnerable to Blood-Brain Barrier Dysfunction?

The hippocampus in the brain is vital to cognitive functions involving learning and memory. In today's open access paper, researchers review the evidence for the hippocampus to be particularly vulnerable to damaging mechanisms, including those involved in aging. It is tentatively suggested that physiological and biochemical differences in the hippocampus point to a greater fragility of the hippocampal blood-brain barrier as a common thread underlying pathological changes observed in aging and Alzheimer's disease. The blood-brain barrier is a specialized layer of cells that wrap blood vessels passing through the central nervous system. Its purpose is to restrict traffic of molecules and cells between the bloodstream and the brain, to maintain the brain's comparative isolation from much of the biochemistry of the rest of the body.

It is well established that the blood-brain barrier becomes dysfunctional in later life, as is the case for all other complex structures in the body. It leaks, allowing cells and molecules into the brain to cause local inflammatory reactions and other damage. The causes of this leakage are a complex web of interactions stretching from fundamental mechanisms of aging through changes in gene expression and altered cell behavior. As for the rest of aging, there is no good map to link what is known of the root causes of aging to what is known of the way in which cells in the blood-brain barrier become dysfunctional. This is why many in the community argue for a greater focus on addressing the root causes rather than on continued efforts to understand how exactly those root causes produce degenerative aging, in detail. If so much time and funding is going to be expended on the problem of aging, let it be on projects that have the hope of producing rejuvenation therapies rather than merely greater understanding.

Vulnerability of the Hippocampus to Insults: Links to Blood-Brain Barrier Dysfunction

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.

Metformin and Galantamine Combination Modestly Improves Sarcopenia Symptoms

Therapies that reuse existing drugs with sizable bodies of human data tend to move more rapidly to the clinic than is the case for better, more ambitious approaches that break new ground. Greater speed in reaching the clinic means a lower cost of development, and this economic incentive is why so much of clinical development consists of drug reuse and only modestly effective therapies. In the case of sarcopenia, the age-related loss of muscle mass and strength, sizable funding is presently devoted to the development of small molecule therapies that do not produce greater gains than resistance exercise. A good deal of what we might think of as muscle aging is in fact disuse. More generally, and not just in the matter of sarcopenia, it would be good to see greater ambition, more development of first in class therapies in the research and development community - but people follow incentives, particularly when a great deal of funding is involved.

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.

Link: https://www.rejuvenatebiomed.com/en/news/clinical-trial-demonstrates-the-therapeutic-potential-of-rjx-01-in-sarcopenia

An Example of Antihypertensive Drug Discovery Based on TRPV2 Biochemistry

The development of drugs to force blood vessels into greater dilation, thereby lowering blood pressure, remains a popular ongoing concern despite the large number of such drugs already in use. Raised blood pressure causes significant downstream harm to the vasculature and surrounding delicate tissues in the body, enough that reductions in mortality can be achieved by forcing blood pressure reductions even without addressing the underlying mechanisms of aging that cause vascular stiffness. The materials here are a good example of the way in which early stage drug discovery takes place these days. Researchers start with a protein or protein interaction, then look for small molecules that (a) stimulate or interfere in that interaction in some way and (b) manage to do so with minimal side-effects and few to no other interactions.

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."

Link: https://www.uab.cat/web/newsroom/news-detail/new-therapeutic-approaches-for-hypertension-through-trpv2-proteins-1345830290613.html?detid=1345911637048

A Lengthy View of Everything that is Wrong with the Drug Development Industry

The primary problems with drug development are self-evident from the data. Firstly the process of drug development has become enormously more expensive over the past seventy years, a period in in which rapid technological progress has diminished the cost and effort required for any task in pharmacology and biotechnology by orders of magnitude. Secondly, the pace at which useful new medicines emerge in the clinic has diminished considerably, over the same period of technological progress in which the bounds of the possible have opened up enormously. The article I'll point out today is well worth reading, a lengthy treatment of these problems and the various viewpoints on what has caused the present dismal state of drug development. I am not sympathetic to the argument that drug development has become inherently harder for technical reasons. I am sympathetic to the viewpoint that regulation and the inherent waste and misaligned incentives present in governments and other large organizations are to blame.

Given that the pace of drug development in the longevity industry is an existential question for all of us, determining how long and in what state of health we will live, it becomes ever more important to ask how the present dismal state of drug development can be changed for the better. How can it be made faster and cheaper to produce new medical technologies? Or to put it another way, how can we get rid of the ball and chain that has been applied to the process of producing new medical technologies? Working within the system has failed dramatically. Some well-funded groups in the US have tried over the past twenty years, a period of time in which the regulatory cost imposed on medical development by the FDA has doubled. Consider the past efforts of FasterCures for example. Given this, and the many other examples of failure to change bad institutions from the inside, I believe that the only viable way forward to create meaningful change in medical regulation in the wealthier regions of the world is to produce competition through medical tourism.

This means more than just a larger medical tourism industry as it presently exists, because while that industry managed to accelerate the acceptance and regulatory approval of first generation stem cell therapies, that change was still too little and too slow. Forms of organization are lacking in the medical tourism industry, which remains small and disorganized. For example, there is a lack of hybrid organizations that combine aspects of venture capital, clinical business, preclinical development, and respected reviewer of data. The Longevitytech.fund (venture capital and clinical business) and the biotech side of the Próspera project (real estate investment, clinical business, clinical trial infrastructure) are examples of steps in this direction. The part that remains missing is a robust way for the medical tourism industry to produce reputable human data, via the existence of organizations that provide reputation, trust, and value for the industry without turning into just another mini-FDA, beholden to its own interests above those of the field.

The pharma industry from Paul Janssen to today: why drugs got harder to develop and what we can do about it

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 article starts out with the premise that it is an increased expense of discovery and development, resulting from structural shifts in the way these processes are conducted, that is the major factor in the problems facing the drug development industry. The author still includes a good, long view of issues on regulatory side of the house. I would argue that those issues are the major factor, both in direct and indirect ways: not just by directly imposing costs, but also by indirectly steering researchers and industry into poor, inefficient strategies. I encourage you to read the whole article.