Fight Aging! Newsletter, July 15th 2024
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- A Correlation Between Telomere Length and Weight-Adjusted Waist Index
- Being Old and in Relatively Good Shape Does Not Equate to Being Healthy
- Notes on the 2024 Longevity Summit Dublin
- Increasing Either Mitochondrial Fission or Fusion Extends Life in Nematode Worms
- Clonal Hematopoiesis of Indeterminate Potential (CHIP) Accelerates Chronic Kidney Disease
- Loss of MEN1 Expression in Osteoblasts Plays a Role in Osteoporosis
- Physical Fitness Influences Brain Health in Part via Effects on Microglia
- Telomerase as a Target in Wet Macular Degeneration
- Towards T Cell Immunotherapies Targeting Senescent Cancer Cells
- Negligible Senescence in the Greenland Shark
- Chronic Inflammation in Early Adulthood Correlates with Worse Cognitive Function in Middle Age
- Launching a Study of Rapamycin in Older Patients with Gum Disease
- TNIK as a Potential Target for Age-Slowing Therapeutics
- Exploring the Biochemistry of Aortic Aneurysm Formation
- Extracellular Vesicle Therapy Promotes Bone Formation in a Mouse Model of Osteoporosis
A Correlation Between Telomere Length and Weight-Adjusted Waist Index
https://www.fightaging.org/archives/2024/07/a-correlation-between-telomere-length-and-weight-adjusted-waist-index/
Epidemiological researchers have for been slowly moving away from body mass index and towards measures that more directly reflect the burden of visceral fat tissue. Waist circumference and measures such as weight-adjusted waist index are now often used. Here, researchers show a correlation between shorter telomere length and larger weight-adjusted waist index; people who are more overweight tend to have shorter telomeres.
Telomere length taken from white blood cells in a blood sample correlates with aging, but only in large studies. It isn't a great measure of biological age, but in principle reflects some combination of (a) replication stress placed upon the immune system, as telomeres shorten with each cell division, and (b) the pace at which replacement immune cells with long telomeres are generated by hematopoietic stem cells. In the case of T cells of the adaptive immune system it also reflects the degeneration of the thymus, as T cells mature in that organ. Degenerative aging will tend to lead to worse stem cell function and greater stress placed upon the immune system, but there is a lot of variability from individual to individual.
Does being overweight accelerate aging? One can mount a good argument that it does, based on a survey of mechanisms involved in aging and how they are altered in overweight individuals. Certain, excess visceral fat tissue appears to increase the pace at which senescent cells accumulate. This is a noteworthy feature of aging, as lingering senescent cells disrupt tissue structure and function via pro-inflammatory signaling. Excess visceral fat tissue also generates chronic inflammation via a range of other mechanisms.
Associations between weight-adjusted-waist index and telomere length: Results from NHANES: An observational study
Telomeres, which are also known as the "protective caps" of chromosomes, are DNA-protein complexes located at the tip of chromosomes consisting of DNA repetitions and a small number of protective binding proteins. They protect chromosomal ends from genomic damage and instability. Telomeres shorten with each cell cycle, and when they become severely short, cells either enter senescence, cell cycle arrest, or undergo apoptosis. Telomere attrition is widely recognized as a prominent hallmark of aging. Telomere attrition has been linked to numerous ailments, including diabetes mellitus, Alzheimer disease, and major cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and heart failure. Moreover, shortened telomeres are connected with an elevated risk of all-cause mortality among the general population.
Obesity poses a significant threat to public health worldwide. However, the most commonly used traditional metric to define being overweight, Body mass index (BMI), cannot distinguish between fat mass and lean mass, nor between central fat and peripheral fat. It is worth noting that weight-adjusted-waist index (WWI) has the potential to compensate for both of these deficiencies. WWI, which is standardized by adjusting the waist circumference (WC) based on body weight, was first proposed in 2018. The initial objective was to construct an obesity index that indicates WC, which exhibits a weak connection with BMI. The aim was to alleviate the obesity paradox of BMI versus mortality. Like telomere length, WWI was found to be directly proportional to age, suggesting its unique function to reflect the age-related alteration of body composition.
This article presents the results of the inaugural study on the relationship between WWI and telomere length in adult populations. The cross-sectional investigation analyzed data from 3479 participants from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2000. To inspect linear and nonlinear correlations, we adopted weighted multiple logistic regression analysis and smooth curve fit, respectively. In addition, threshold effects and subgroup analyses were accomplished. In the fully adapted model, a significant adverse association of WWI with telomere length was detected. The adverse correlation remained consistent across all subcategories. We also discovered an inverted U-shaped curve linking WWI and telomere length, with a conspicuous inflection point. The inflection point suggests that controlling WWI within an optimum range might be essential for aging and health.
Being Old and in Relatively Good Shape Does Not Equate to Being Healthy
https://www.fightaging.org/archives/2024/07/being-old-and-in-relatively-good-shape-does-not-equate-to-being-healthy/
Aging is by definition a loss of function and capacity, an accumulation of damage. A person can certainly turn out to be in much better shape than equivalently aged peers in later life, via some combination of lifestyle choices, proactive use of medical resources, and a little good fortune. But that doesn't mean that this individual is healthy in comparison to the younger version that existed decades ago. Again, aging is by definition a loss of function and capacity, a disruption of the normal healthy operation of tissues. An old person is unhealthy when compared to his or her younger self.
Today's research materials make this point in the course of presenting new data on the prevalence of heart valve disease in the older population. As is the case for recent research demonstrating that many people in their 40s and 50s exhibit the early development of atherosclerotic lesions, hidden and lacking evident symptoms, here it was found that more than a quarter of older people lacking evident symptoms do in fact have heart valve disease. This asymptomatic stage of dysfunction is a foundation for later, more severe, and more evident cardiovascular disease.
More than a quarter of 'healthy' over-60s have heart valve disease, according to new research
The sheer scale of undiagnosed heart valve disease in our ageing population has been revealed for the first time, thanks to new research. More than a quarter of healthy and symptom-free over 60s examined in the study were found to have previously undetected heart valve disease. "This study focused on understanding how widespread heart valve issues of any severity are among healthy, symptom-free adults without any known heart diseases. We examined almost 4,500 individuals aged 60 and older from three regions in the UK: Norfolk, West Midlands, and Aberdeen, using echocardiography, which is an ultrasound of the heart."
"Our findings showed that more than 28% of these adults had some form of heart valve disease, although reassuringly it was only mild in the majority of the cases. The data also indicated that age was the main factor associated with these heart valve problems, meaning that the older a person is, the higher their chance of having a significant valve issue. The main problems are caused by the valve not opening fully (valve stenosis) which restricts the flow of blood, or the valve not closing properly (valve regurgitation) which means blood can leak back in the wrong direction. These problems can put extra strain on the heart and make the heart work harder. Over time, it can increase the risk of having a heart attack, stroke, and other heart conditions."
Prevalence of asymptomatic valvular heart disease in the elderly population: a community-based echocardiographic study
With an ageing population, the presence of asymptomatic valvular heart disease (VHD) in the community remains unknown. This was a prospective cohort study conducted between 2007 and 2016 in the UK. Asymptomatic patients with no prior indication for echocardiography were invited to participate and evaluated with a health questionnaire, clinical examination, and transthoracic echocardiography. A total of 10,000 individuals were invited through their general practices. A total of 5429 volunteered to participate, of whom 4237 were eligible for inclusion. VHD was diagnosed in more than a quarter of patients (28.2%). Age is strongly associated with an increased incidence of significant VHD.
Notes on the 2024 Longevity Summit Dublin
https://www.fightaging.org/archives/2024/07/notes-on-the-2024-longevity-summit-dublin/
I attended this year's Longevity Summit Dublin in June, hosted by the Longevity Escape Velocity (LEV) Foundation folk, but was so buried in work that there was no chance I would be able to take comprehensive notes for later formatting into a post here. Fortunately there are a good number of patient advocates in the community who can do just as good a job as I might, were I less encumbered, and thus Lifespan.io has published notes on some of the highlights from the conference.
The Longevity Summit Dublin is, if you like, the spiritual successor to the Strategies for Engineered Negligible Senescence (SENS) conference series of past years: scientists presenting novel research aimed at the goal of treating aging as a medical condition; biotech startups showcasing their programs of development relevant to the treatment of aging; patient advocates arguing for more funding and faster progress for all of the above. It is well worth attending if this is an area of research and development that interests you.
Four Days of Longevity in Dublin: Conference Highlights
The first day began with a "pre-session" before the official opening, and the very first talk set an interesting tone. It was given by Michael Suk, the newly elected chair of the American Medical Association (AMA)'s Board of Trustees. The AMA is the biggest organization of medical doctors in the US, and having its leader talk at a longevity conference is an important event and an encouraging sign of our field inching closer to the mainstream. Suk, through a remote connection, praised the recent scientific advances that bring us closer to personalized medicine that would allow for continuing healthspan extension. "The work you do here," he said, "has the potential to change lives, to offer hope where there is none, and to redefine the future of healthcare. Together, we are building a future where technology and compassion go hand in hand, where surgical care is not just about precision, but about people, and where the promise of a longer, healthier life is within reach for all."
Aubrey de Grey welcomed the participants and expanded on longevity escape velocity (LEV), the concept he has been promoting for decades that gave the name to his foundation. LEV means buying time by eliminating age-related damage (another concept that de Grey pioneered and is now entering the mainstream): "If you take someone who is, let's say, 60 years both chronologically and biologically, and you rejuvenate them reasonably well so that they're back to being biologically 40, then they won't be biologically 60 again until they're 80." However, some types of damage are harder to tackle, and they will continue to accumulate, but their effect will not be as devastating as today's combined effects of all types of damage. Hopefully, during those 20 extra years of life, geroscientists "will have been continuing to improve this rejuvenation arsenal. The idea is that there's some finite, in fact quite modest, minimum rate at which we need people like the people in this room to be improving the comprehensiveness of rejuvenation technologies in order to stay one step ahead of the problem."
Revel Pharmaceuticals is one of those brave small companies to literally boldly go where no one has gone before: in this case, towards reversing the molecular damage produced by advanced glycation end products (AGEs). Like their name suggests, AGEs accumulate with age in blood and tissues, causing inflammation and the stiffening of the extracellular matrix by binding to molecules like collagen. Aaron Cravens, Revel's CEO, told the audience that his company is after a specific AGE, carboxymethylysine (CML). It exists in two forms: a free form present in cells and a bound form that accumulates in the extracellular matrix (for instance, in arterial walls). "The body has no physiological means of removing this," Cravens said. Revel built an enzyme engineering platform to develop bespoke enzymes. Currently, it focuses on removing the free-floating form of CML. It strongly contributes to inflammation, in particular by binding to the RAGE receptor and initiating inflammatory signaling.
Michael Ringel of the Boston Consulting Group talked about the recent trends in the longevity field. After decades of not taking geroscience seriously, there is apparently a growing understanding in society that investigating the biology of aging is the only way to ward off the economic threats of population aging and to meaningfully increase human lifespan. If we do nothing, global resources might be devastated by the need to care for the increasingly aged population, exacerbated by slumping birth rates. However, even a slight slowing of the rate of aging would bring unprecedented prosperity, adding hundreds of trillions to the global economy over the course of a decade.
The Rising Star Award this year went to Alexander Fedintsev from the Radical Life Extension Group. In his talk, Fedintsev proposed a new hallmark of aging: clonal hematopoiesis of indeterminate potential (CHIP). Clonal hematopoiesis is a condition in which a single hematopoietic stem cell (HSC) acquires genetic mutations that give it a growth advantage, allowing it to expand clonally within the bone marrow. This results in a significant proportion of blood cells being derived from this single mutated stem cell rather than from a diverse population of HSCs. Currently, we don't have good tools to combat CHIP. However, prolonged inhibition of the pro-inflammatory cytokine IL-6 has shown some promise, including in non-human primates. Answering a question about how safe lifelong IL-6 inhibition is, Fedintsev noted that rheumatoid arthritis patients receive such therapy, which only causes a slight increase in infections but is associated with less cardiovascular risk.
The Lifetime Achievement Award was given this year to Maria Blasco, a veteran geroscientist whose contribution to the longevity field is formidable. After a short ceremony Maria proceeded to give a keynote talk on telomeres, the leading topic of her research for the last three decades. Maria described some of the most important experiments with telomeres. For instance, telomerase deficiency in mice causes accelerated aging, while transgenic mice with extra-long telomeres live longer and, importantly, get less cancer, which is the leading cause of death in lab mice. These mice also showed significant improvements in healthspan: better metabolism, less cognitive decline, less osteoporosis, and so on. Another study that Maria mentioned might provide an explanation of why turning back telomerase expression seems to lower the risk of cancer instead of elevating it: shorter telomeres cause chromosomal instability, which increases the risk of oncogenic mutations. Genetically engineered telomerase-expressing mice were more protected from cancer even when challenged with oncogenic mutations.
Melissa King has over two decades of experience in business, non-profits, and public affairs. About two years ago, she co-founded Healthspan Action Coalition with another veteran medical research advocate, Bernard Siegel. Melissa has steered important campaigns and projects in patient advocacy and biomedical research funding. For example, she led a successful ballot initiative in California to secure 8.5 billion in funding for the California Institute for Regenerative Medicine, which specializes in stem cell research. Patient advocacy, Melissa argued, is impressively effective in mobilizing public opinion and funds for health research initiatives. Now is the time to apply the principles of patient advocacy to prolonging healthspan. After all, when it comes to aging, every person on the planet is a patient. This creates a potential for a truly massive movement.
Increasing Either Mitochondrial Fission or Fusion Extends Life in Nematode Worms
https://www.fightaging.org/archives/2024/07/increasing-either-mitochondrial-fission-or-fusion-extends-life-in-nematode-worms/
The primary function of mitochondria is production of the chemical energy store molecule adenosine triphosphate (ATP) to power cell activity, though mitochondria are also integrated into many core cellular processes. Loss of mitochondrial function is an important determinant of the pace of aging, and mitochondrial dysfunction is characteristic of cells in aged tissues. A cell contains hundreds of mitochondria, these organelles descended from the first ancient symbiotic bacteria to take up residence in what would become the ancestor of all eukaryotes. Mitochondria retain an atrophied bacterial genome, and can replicate like bacteria. They also frequently fuse together and promiscuously pass around component parts. The quality of mitochondria is assured in part by these ongoing dynamics, but more importantly by mitochondrially-targeted autophagy, known as mitophagy, that flags dysfunctional mitochondria for delivery to a lysosome where they are broken down and recycled.
The balance between mitochondrial fission and fusion appears important to mitochondrial function, though there is some debate as to why exactly this is the case. Too many small mitochondria and too many large mitochondria may both be bad, and for different reasons. The second order consequences of changes in the complex regulation of mitochondrial fission and fusion are poorly mapped and understood, especially when it comes to how these changes interact with mitophagy and the capacity to remove dysfunctional mitochondria before they cause harm to the cell. Today's open access paper provides an example of this lack of understanding, as the authors are surprised to note that increasing expression of fission regulators has much the same outcome as increasing expression of fusion regulators. In both cases, mitochondria appear to exhibit dynamics associated with greater fission, and the life span of engineered nematode worms is increased. This is not an intuitive outcome.
Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity
The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease.
In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan.
Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains.
Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.
Clonal Hematopoiesis of Indeterminate Potential (CHIP) Accelerates Chronic Kidney Disease
https://www.fightaging.org/archives/2024/07/clonal-hematopoiesis-of-indeterminate-potential-chip-accelerates-chronic-kidney-disease/
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related state in which a hematopoietic stem cell suffers a mutation that gives it and its descendants replication advantages over their peers. Mutations of this nature spread throughout cell populations in an overlapping, layered way as they occur, a form of somatic mosaicism, but occurring in hematopoietic and immune cells. Like somatic mosaicism more generally, this has the look of a problem that should cause undesirable consequences. Drawing solid connections between CHIP and specific age-related diseases is a work in progress, however.
CHIP originated as the description of an early stage of dysfunction leading to leukemia, in that clonal expansion of potentially cancerous mutations in hematopoietic cells is observed. The connection to cancer is thus fairly robust. There is also less extensive evidence for CHIP to contribute to the progression of many age-related diseases via an increase in the chronic inflammation of aging. Much of the discussion to date has involved cardiovascular disease, but in today's open access paper, researchers present evidence for CHIP to accelerate the progression of chronic kidney disease. In both of these cases, inflammation is the easy answer when it comes to questions about mechanisms, but that doesn't mean it is definitely the case.
Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression
Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the clonal expansion of blood cells carrying somatic mutations in specific driver genes. An age-related disorder, CHIP is rare in the young but its prevalence increases rapidly in older adults, with at least 10% of individuals aged 65 and older affected. Recent studies have identified a causal role for CHIP in several chronic diseases of aging including atherosclerotic cardiovascular disease, heart failure, gout, liver fibrosis and cirrhosis, osteoporosis, and chronic obstructive pulmonary disorder (COPD).
CHIP is also recognized as a risk factor for acute kidney injury (AKI) severity and non-recovery. Mouse model evidence and human genetic studies point to inflammation as the key mediator of the CHIP-associated risk in each of these conditions. A hallmark feature of chronic kidney disease (CKD), chronic inflammation confers higher risks of kidney failure in CKD patients. CHIP has been associated with incident kidney function decline in the general population, though it is not clear whether the inflammatory burden of CHIP would meaningfully intensify the already-inflamed CKD state and affect clinical outcomes.
In this study, we first examined the prospective associations between CHIP and CKD progression events in four large CKD cohorts, totaling 6,216 individuals: the Chronic Renal Insufficiency Cohort (CRIC), the African American Study of Kidney Disease (AASK), subjects with CKD from the BioVU biorepository, and the Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT). We then used Mendelian randomization as an orthogonal method to assess the contribution of CHIP to estimated glomerular filtration rate (eGFR) decline. Finally, we evaluated the effect of experimental Tet2-CHIP on kidney function in a mouse model of CKD.
n the present work, we identify that non-DNMT3A CHIP is associated with a greater risk of kidney function decline in individuals with CKD, both when examining incident 50% eGFR decline or kidney failure events and annualized eGFR slopes. In Mendelian randomization analysis, a genetic predisposition for CHIP development was associated with a faster eGFR decline in those with CKD and diabetes. Additionally, in a Tet2-CHIP mouse model - the most common type of non-DNMT3A CHIP - dietary adenine administration led to more pronounced kidney functional impairment, inflammatory cell infiltration into kidney parenchyma, increased cytokine expression, and development of renal fibrosis when compared to mice without CHIP mutations fed the same diet. These findings are in line with our pilot study and with our work identifying non-DNMT3A CHIP as a risk factor for incident kidney function decline in the general population as well as for impaired recovery after AKI.
Loss of MEN1 Expression in Osteoblasts Plays a Role in Osteoporosis
https://www.fightaging.org/archives/2024/07/loss-of-men1-expression-in-osteoblasts-plays-a-role-in-osteoporosis/
Bone tissue is constantly remodeled, created by osteoblasts and broken down by osteoclasts. Osteoporosis, a progressive age-related loss of bone density that leads to fracture and incapacity, occurs due to an imbalance between these cell populations that favors osteoclasts over osteoblasts. Researchers here note that Men1 expression declines with age in osteoblasts, and may be an important proximate cause of osteoporosis via mechanisms that include increased cellular senescence in bone tissue. Finding ways to increase Men1 expression in bone-related cell populations may prove to be a useful point of intervention.
Recent evidence suggests an association between age-related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age-related osteoporosis and the mechanism remain unknown. Results revealed that age-related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast-specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age-related osteoporosis.
Histomorphometrically, Men1-knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age-related osteoporosis. Loss of Men1 induces cellular senescence via mTORC1 activation and AMPK suppression, rescued by metformin treatment. In bone morphogenetic protein-indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age-related osteoporosis and that osteoblast-specific inducible Men1-knockout mice offer a promising model for developing therapeutics for age-related osteoporosis.
Physical Fitness Influences Brain Health in Part via Effects on Microglia
https://www.fightaging.org/archives/2024/07/physical-fitness-influences-brain-health-in-part-via-effects-on-microglia/
Microglia are innate immune cells resident in the central nervous system, analogous to macrophages elsewhere in the body, but with an extended portfolio of activities that include assisting in management of synaptic connections between neurons. In recent years, researchers have placed an ever greater focus on the behavior of microglia, particularly their contribution to chronic inflammatory signaling in the brain, in the context of aging and neurodegenerative disease. Aging is characterized by overly active inflammatory microglia and greater numbers of senescent microglia. Ways to clear and regenerate the microglial population, or otherwise change their behavior for the better, have shown some promise in animal models. Here, researchers review the evidence for some of the benefits of physical fitness, improved cognitive function and slowed cognitive aging, to be mediated by favorable changes in the behavior of microglia.
It is largely accepted that physical exercise (PE) can promote brain health and cognitive function. Reports in humans show that moderate to vigorous PE can enhance cognition. However, the cellular mechanisms that underlie this phenomenon are still an active area of exploration. Traditionally, studies have examined how PE regulates wiring of neuronal connections to enhance cognitive function. However, recent focus has shifted toward how exercise may regulate inflammation and the immune response in the central nervous system (CNS).
Microglia are the resident immune cells of the CNS responsible for mediating inflammatory responses, tissue maintenance, and synapse remodeling. Microglia are key mediators of neuroinflammatory processes and play a role in maintaining brain homeostasis in healthy and pathological settings. Here, we explore the evidence suggesting that physical activity has the potential to regulate microglia activity in various animal models. We emphasize key areas where future research could contribute to uncovering the therapeutic benefits of engaging in physical exercise.
Telomerase as a Target in Wet Macular Degeneration
https://www.fightaging.org/archives/2024/07/telomerase-as-a-target-in-wet-macular-degeneration/
In wet macular degeneration, excessive formation of leaky blood vessels in the retina leads to photoreceptor cell death and blindness. Current treatments try to sabotage part of the signaling system responsible for angiogenesis, the process of blood vessel creation. Here, researchers instead look at inhibition of telomerase after finding increased expression of telomerase in mouse models of the condition. This is interesting, but it is worth remembering that telomerase dynamics are very different in mice and humans. Mice normally express telomerase in a range of somatic cells, where humans do not. There is some doubt that mechanisms involving telomerase that are discovered and characterized in mice will prove to be usefully relevant in humans in the same way.
Choroidal neovascularization (CNV) is the principal driver of blindness in neovascular age-related macular degeneration (nvAMD). Increased activity of telomerase has been associated with endothelial cell proliferation, survival, migration, and invasion in the context of tumor angiogenesis. Expanding on this knowledge, we investigated the role of telomerase in the development of CNV in a mouse model. We observed increased gene expression and activity of telomerase in mouse CNV. Genetic deficiency of the telomerase components, telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc) suppressed laser-induced CNV in mice. Similarly, a small molecule inhibitor of TERT (BIBR 1532), and antisense oligonucleotides (ASOs) targeting Tert and Terc reduced CNV growth.
Bone marrow chimera studies suggested that telomerase activity in non-bone marrow-derived cells is crucial for the development of CNV. Comparison of BIBR 1532 with VEGF neutralizing therapeutic strategy in mouse revealed a comparable level of angiosuppressive activity. However, when BIBR and anti-VEGF antibodies were administered as a combination at sub-therapeutic doses, a statistically significant suppression of CNV was observed. These findings underscore the potential benefits of combining sub-therapeutic doses of BIBR and anti-VEGF antibodies for developing newer therapeutic strategies for NV-AMD. Telomerase inhibition with BIBR 1532 suppressed induction of multiple cytokines and growth factors critical for neovascularization.
In conclusion, our study identifies telomerase as a promising therapeutic target for treating neovascular disease of the eye and thus provides a proof of principle for further exploration of telomerase inhibition as a novel treatment strategy for nvAMD.
Towards T Cell Immunotherapies Targeting Senescent Cancer Cells
https://www.fightaging.org/archives/2024/07/towards-t-cell-immunotherapies-targeting-senescent-cancer-cells/
A robust discussion is underway in the cancer research community regarding the merits of targeting senescent cells for destruction as a part of cancer therapy. While it is generally agreed that clearing lingering senescent cells following successful treatment with present cancer therapies is a good idea, as those senescent cells contribute to the greater burden of age-related disease and mortality observed in cancer survivors, it is less clear that destroying senescent cancer cells during treatment of the cancer will always provide a net benefit. Those senescent cells can in some cases contribute to the destruction of the cancer rather than enable its growth. Nonetheless, researchers here argue that adapting T cell immunotherapies to target senescent tumor cells is a promising avenue of investigation.
The exploitation of the patient's immune system to eliminate cancer cells has long been tested through the development of innovative strategies with remarkable success and high expectations. Our growing understanding of the immune system has allowed the design of novel anticancer therapies. However, tumor cells are generally poor antigen-presenting cells, evading the immune response in early stages of the pathophysiology and restricting immunotherapeutic efficacy to only a minor group of cancers. Nevertheless, targeting of senescent cells in the context of cancer and aging may upsurge as an alternative to this critical limitation, through the selective activation of a T cell-specific response against senescent cells within the tumor or its vicinity.
Recent evidence supports the use of tumor-associated senescent cells (TASCs) as sources of peptide antigens and adjuvants for anticancer vaccine development. Their senescence-associated secretory phenotype (SASP) provides abundant release of stimulatory cytokines, which, in conjunction with high levels of antigen presentation, generates a robust tumor specific T cell response. As discussed here, this approach will potentiate their adjuvanticity in cancer targeting, allowing the design of stronger and directed immunotherapeutic strategies. Moreover, since cancer and senescent cells share common antigens, this immunotherapeutic approach could also be effective against aging and age-related diseases. Therefore, cancer immunotherapy based on TASCs and other types of senescent cells may achieve exciting outcomes beyond cancer therapy.
Negligible Senescence in the Greenland Shark
https://www.fightaging.org/archives/2024/07/negligible-senescence-in-the-greenland-shark/
You may recall that Greenland sharks are extremely long-lived, a trait only comparatively recently discovered as, like many marine species, these sharks are nowhere near as well studied as tends to be the case for larger land animals. Researchers have now started in on the process of trying to understand why this is the case. As reported here, initial measurements of muscle metabolism show little variation with age. An absence of declining function with age over near all of a lifespan is characteristic of many long-lived species. It remains to be seen as to whether studying the biochemistry of these unusually long-lived species will yield means of enhancing longevity in humans in the near term of the next few decades. It is too soon to say, even if commenting on the much more extensive study of long-lived mammalian species such as the naked mole-rat.
Greenland sharks (Somniosus microcephalus) are the longest living vertebrate with an expected lifespan of at least 270 years and possible lifespan beyond 500 years. Previously it was thought that this long lifespan was due to the shark's cold environment and minimal movement, but the factors behind this species extreme longevity appear to be far more complex - prompting researchers to investigate alternative theories. "Most species show variation in their metabolism when they age. We want to determine if Greenland sharks also show this traditional sign of aging or if their metabolism remains unaltered over time."
To measure the metabolism of the sharks, researchers conducted enzyme assays on preserved muscle tissue samples from Greenland sharks. They measured the metabolic activity of these enzymes with a spectrophotometer across a range of different shark ages and environmental temperatures. Surprisingly, researchers found no significant variation in muscle metabolic activity across different ages, suggesting that their metabolism does not appear to decrease over time and may play a key role in their longevity. The results of this study also show that the Greenland shark's metabolic enzymes were significantly more active at higher temperatures. "This would suggest that the shark's red muscle metabolism is not specially adapted for the polar environment, otherwise we would have expected to see less of a temperature related difference in activity."
Chronic Inflammation in Early Adulthood Correlates with Worse Cognitive Function in Middle Age
https://www.fightaging.org/archives/2024/07/chronic-inflammation-in-early-adulthood-correlates-with-worse-cognitive-function-in-middle-age/
Short-term inflammation is a necessary part of the immune response to pathogens, injury, and problematic cells. Lasting unresolved inflammation is harmful, however. It is a feature of aging, but can also occur to significant degrees in earlier life as a result of autoimmunity or being very overweight. Researchers here show that early adult chronic inflammation correlates with worse cognitive function nearly two decades later. One can debate the degree to which this is a measure of accelerated degenerative aging versus the progression of existing conditions, but it is certainly true that chronic inflammation is to be avoided and minimized to the degree that it is possible to do so.
There are two kinds of inflammation. Acute inflammation happens when the body's immune response jumps into action to fight off infection or an injury. It is localized, short-term and part of a healthy immune system. Chronic inflammation is not considered healthy. It is a low-grade inflammation that lingers for months or even years throughout the body. It can be caused by autoimmune disorders like rheumatoid arthritis or multiple sclerosis, physical stress or other causes. Symptoms of chronic inflammation include joint pain or stiffness, digestive problems, and fatigue.
The study involved 2,364 people age 24 to 58. They were followed for 18 years. Participants' inflammation levels were measured at the start of the study and three more times throughout the study. The study looked at levels of C-reactive protein (CRP) in the blood. CRP is produced by the liver and increases when there is inflammation in the body. Researchers divided participants into three groups based on inflammation levels: consistently higher, moderate or increasing and lower stable. Of the total participants, 911 people, or 39%, had consistently higher inflammation; 381 people, or 16%, had moderate or increasing inflammation; and 1,072, or 45%, had lower stable inflammation.
Five years after their last inflammation measurement, participants were given six tests to examine thinking and memory skills. On a test that measures processing speed and memory, participants were given a key showing numbers and corresponding symbols. They then drew those symbols on a separate list of random numbers as quickly as possible. Of those in the low group, 10% had poor cognitive performance, compared to 21% in the middle group and 19% in the high group. After adjusting for factors such as age, physical activity and total cholesterol, researchers found that both the high and moderate groups were more likely to have poor performance in processing speed and executive function. For processing speed, researchers found that those in the moderate group were more than two times more likely to have poor performance and those in the highest group were nearly two times more likely to have poor performance than those in the lowest group. For executive function, those with the highest CRP levels had a 36% higher risk of poor performance.
Launching a Study of Rapamycin in Older Patients with Gum Disease
https://www.fightaging.org/archives/2024/07/launching-a-study-of-rapamycin-in-older-patients-with-gum-disease/
Based on the animal data, mTOR inhibition by rapamycin is the best of the presently well studied pharmacological approaches to slow aging. Rapamycin is cheap, has decades of safety data, and produces a greater extension of life span in animal models than exercise. Sad to say, but improving on the benefits of exercise remains the low bar by which we can judge and reject the vast majority of efforts to slow the progression of aging. Human studies of rapamycin in the context of aging have yet to be conducted in any extensive manner, despite a fair amount of off-label use. So it is pleasant to see that one group has recently obtained funding to conduct a study in older people with periodontal disease; the specific condition that is the target of the study is less important than the range of data on biomarkers relevant to general health and aging that will be collected.
A clinical trial is starting to test a drug taken by many so-called longevity enthusiasts. Rapamycin was first approved by the FDA for transplant patients in the 1990s. At high doses, it suppresses the immune system. At low doses, it seems to help tamp down inflammation. It works by inhibiting a pathway in the body called mTOR, which appears to be key to healthy aging. Rapamycin is not approved for pain or anti-aging, though doctors can prescribe it off-label. Researcher Matt Kaeberlein has surveyed about 300 people who take low doses, and many report benefits. But anecdotes are no replacement for science, and that's where dental group at the University of Washington comes in. The researchers have FDA approval to test rapamycin in patients with gum disease, a common condition that tends to accelerate with age.
There is already some evidence from transplant patients that rapamycin may help improve oral health, and as part of the study, researchers will also measure changes in participants' microbiomes and their biological clocks. The study will enroll participants over the age of 50 who have gum recession. They will take the drug for eight weeks. The researchers think of gum disease as a kind of canary in the coal mine. It's linked to a higher risk of heart disease, for instance, so they may share a common root cause. The researchers have received grants to conduct this trial, which could open the door to further studies to determine whether rapamycin can help slow down other age-related diseases.
TNIK as a Potential Target for Age-Slowing Therapeutics
https://www.fightaging.org/archives/2024/07/tnik-as-a-potential-target-for-age-slowing-therapeutics/
The paper noted here is an illustrative snapshot of one tiny part of the search for new mechanisms of action that takes place constantly in academia and the pharmaceutical industry. Cell metabolism remains an only partially charted expanse, the high points filled in, and mostly a blank canvas in between. The poorly explored regions of metabolism could yield any number of interesting points of intervention, each a starting point for the present industry-standard approach of small molecule drug discovery. That said, there isn't that much of an incentive to pour funds into search initiatives because the odds of success in the current paradigm are very low. The vast majority of discoveries do not lead to even marginally useful drugs. Hence there is considerable interest at the present time in the development of new computational infrastructure technologies that can reduce the cost of discovery in some way.
Traf2- and Nck-interacting kinase (TNIK) has emerged as a key regulator of pathological metabolic signaling in several diseases and is a promising drug target. Originally studied for its role in cell migration and proliferation, TNIK possesses several newly identified functions that drive the pathogenesis of multiple diseases. Specifically, we evaluate TNIK's newfound roles in cancer, metabolic disorders, and neuronal function. We emphasize the implications of TNIK signaling in metabolic signaling and evaluate the translational potential of these discoveries.
TNIK signaling appears to converge on four critical hallmarks of aging: cellular senescence, deregulated nutrient sensing, chronic inflammation, and altered intercellular communication. TNIK's contribution to these processes implicate it as a possible contributor to aging-related pathology, particularly by promoting conditions like cancer and metabolic dysregulation. Thus, as aging has been revealed to increase the incidence and severity of the aforementioned diseases in this opinion article, an interesting hypothesis would be whether TNIK dysregulation contributes to the aging process itself or is a consequence of it.
Exploring the Biochemistry of Aortic Aneurysm Formation
https://www.fightaging.org/archives/2024/07/exploring-the-biochemistry-of-aortic-aneurysm-formation/
An aneurysm is a weakened section of a major blood vessel that expands and grows into a balloon-like structure. Rupture is often fatal. Aneurysms tend to form in specific locations, and researchers here ask why this is the case. Associating a characteristic set of changes in cell biochemistry with the formation of aneurysms in mice is a first step on a long road towards better detailed understanding of the mechanisms involved, and the development of interventions to prevent formation of aneurysms.
A vascular dilatation in the aorta can be life-threatening if it bursts. These so-called aortic aneurysms typically form in the same sites of the large blood vessel: either on the upper arch or in the abdominal cavity. In order to find out what distinguishes the repeatedly affected vascular regions from others, researchers developed a method to specifically examine the endothelium of the aorta: the innermost layer of the blood vessel. "We know from other vascular diseases such as arteriosclerosis that there are changes in this innermost layer long before symptoms appear."
The researchers analyzed the gene activity at different sites of the aorta and compared the sites where aneurysms frequently form with those that don't show this tendency. "We identified certain patterns of upregulated genes in the sites where dilatations frequently form. These remarkably active genes affect, for example, changes in the extracellular matrix, the formation of new blood vessels and some inflammatory reactions." Such genetic abnormalities are also found in tissue from human aneurysms. The researchers also determined the stiffness of the endothelium in the healthy aortic samples. The less elastic the endothelium, the more detrimental it is to vascular health. They proved that the endothelium was stiffer in the sites where aneurysms frequently develop than in the control areas.
The team used an established model of a knock-out mouse that tends to form aneurysms due to a targeted genetic modification. If high blood pressure is additionally induced in these mice, aortic aneurysms form. They compared the genetic activity in the aortic endothelium of the genetically modified mice without aneurysm with that of mice that had developed an aneurysm due to added high blood pressure. "In the mice with aneurysms, we found a much greater degree of gene alterations that belong to the same category as the gene alterations in healthy mice. In the mice with an aneurysm, the vessel wall was also altered." The researchers conclude that the sites where aneurysms frequently form are weak points from the outset. We don't know exactly why this happens - perhaps it has to do with the mechanical conditions and the blood flow there, or perhaps the altered gene activity at these sites is inherited from birth." The latter seems plausible, as the aorta develops at different heights from different embryonic precursor cells.
Extracellular Vesicle Therapy Promotes Bone Formation in a Mouse Model of Osteoporosis
https://www.fightaging.org/archives/2024/07/extracellular-vesicle-therapy-promotes-bone-formation-in-a-mouse-model-of-osteoporosis/
Extracellular vesicles for use in therapy can be derived from engineered cells in order to adjust their contents in favorable ways. Here, researchers derive vesicles from genetically engineered osteoblasts in order to promote bone formation in a mouse model of osteoporosis. Osteoporosis is the name given to the age-related loss of bone mineral density. Bone is constantly remodeled, deposited by osteoblast cells and removed by osteoclast cells. In youth these activities are balanced, but the molecular damage of aging produces changes that favor osteoclasts. The result is a steady loss of bone density, leading to brittle, fracture-prone bones. Any approach that restores the balance between osteoblasts and osteoclasts is likely to work, even if it is essentially compensatory rather than addressing the causes of the problem.
This research investigated the role of WIF1 in controlling the osteogenic differentiation stage of the osteoblast precursor cell line (MC3T3-E1 cells) and assessed its potential therapeutic impact on osteoporosis. Using MC3T3-E1 cells, the researchers found that Wif1 expression increased significantly during the terminal stage of osteoblast differentiation, indicating its role as a marker gene in regulating osteogenesis. Knockdown of Wif1 reduced mineralization and osteogenic potential, while Wif1 overexpression enhanced osteogenic differentiation. Furthermore, Wif1 overexpression activated mitophagy, as evidenced by increased autophagosome formation around mitochondria.
The study also explored the therapeutic potential of extracellular vesicles (EVs) derived from Wif1-overexpressing osteoblasts. These EVs significantly promoted osteogenesis in bone marrow mesenchymal stem cells (BMSCs) in vitro and demonstrated bone-targeting capabilities in vivo. In a mouse model of osteoporosis induced by ovariectomy, treatment with EVs derived from Wif1-overexpressing osteoblasts reversed bone loss, highlighting their potential as a therapeutic intervention for osteoporosis. These findings underscore the significance of Wif1 in bone biology and suggest its potential as a therapeutic target for osteoporosis.