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- Allotopic Expression of Mitochondrial Gene ATP8 in Mice
- cBIN1 Gene Therapy Reverses Heart Failure
- Transcriptional Trajectories of Aging in Nematode Worms
- GDF-15 Expression is Induced by Inflammatory Cell Stress and Promotes Aging
- Nutrient Processing Differences in Exhausted T Cells
- How Might the Gut Microbiome Contribute to Heart Failure?
- Type 2 Diabetes Makes Atherosclerosis Worse by Changing Plaque Structure
- Cellular Senescence in the Context of Inducing Hair Regrowth
- Autoantibodies as Pathological Agents Beyond Autoimmune Conditions
- GDF-15 as a Biomarker of Aging
- Delivery of Platelet Factor 4 Rejuvenates Hematopoietic Stem Cell Function
- Inflammation as an Important Mechanism in the Role of Growth Hormone in Aging
- Nuclear Lipid Droplets as a Hallmark of Aging
- Thoughts on the Hallmarks of Aging in Comparative Biology
- Visceral Fat Correlates with the Burden of Amyloid and Tau in the Aging Brain
Allotopic Expression of Mitochondrial Gene ATP8 in Mice
https://www.fightaging.org/archives/2024/12/allotopic-expression-of-mitochondrial-gene-atp8-in-mice/
Every cell contains hundreds of mitochondria, vital to cell function. These are the evolved descendants of ancient symbiotic bacteria, and contain a small remnant genome, the mitochondrial DNA. Most of the original mitochondrial DNA has migrated to the cell nucleus to be incorporated into the nuclear DNA, but a few genes remain. Unfortunately mitochondrial DNA is less well protected and more prone to damage than nuclear DNA, and loss of function can lead to malfunctioning mitochondria that harm the cell. This is thought to be an important contribution to age-related loss of mitochondrial function, one of the contributing causes of degenerative aging.
Scientists at the SENS Research Foundation, now the Longevity Research Institute since the merger with Lifespan.io, have long been working on allotopic expression of mitochondrial genes, meaning to place a copy of these genes into the nuclear DNA, suitably altered such that the proteins can find their way back to the mitochondria. A backup source of necessary proteins would render mitochondrial DNA damage irrelevant to cell function. This is a challenging project, and given the limited funds available to date, has been achieved for only a few of the thirteen remaining mitochondrial genes. But progress has been made, and today's research materials describe an important step forward. Researchers have created a genetically engineered mouse lineage in which allotopic expression of ATP8 clearly works to provide the ATP8 protein needed in mitochondria.
Nuclear Expression of a Mitochondrial Gene in Mice
Previously, the same team had achieved promising results in vitro, but finding a suitable animal model proved difficult: mitochondrial DNA (mtDNA) genes are so essential that mutations in them usually render mice non-viable. However, a particular strand of mice exists that harbors a relatively benign mutation in ATP8, a gene encoding a subunit of the ATP synthase complex, which causes only a mildly pathologic phenotype. Alongside those mutants, wild-type mice were used as controls.
The team synthesized a nuclear-compatible version of ATP8 and inserted it into the ROSA26 locus, a well-characterized "safe harbor" site in the mouse genome. This locus is widely used in genetic engineering because it allows stable organism-wide expression of inserted genes without interfering with other essential genomic functions. The researchers had to overcome significant technical challenges to achieve nuclear expression of a gene that is normally expressed in mitochondria (allotopic expression) and to make the protein transferrable to mitochondria. Eventually, their efforts paid off: allotopic ATP8 was able to compete with mitochondrial ATP8 even in wild-type mice and outperformed the mutant ATP8. The allotopic gene was expressed in all the tissues that the researchers tested, and the protein successfully integrated into the mitochondrial machinery.
Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo
Replicative errors, inefficient repair, and proximity to sites of reactive oxygen species production make mitochondrial DNA (mtDNA) susceptible to damage with time. We explore in vivo allotopic expression (re-engineering mitochondrial genes and expressing them from the nucleus) as an approach to rescue defects arising from mtDNA mutations. We used a mouse strain C57BL/6J(mtFVB) with a natural polymorphism in the mitochondrial ATP8 gene that encodes a protein subunit of the ATP synthase. We generated a transgenic mouse with an epitope-tagged recoded mitochondrial-targeted ATP8 gene expressed from the ROSA26 locus in the nucleus and used the C57BL/6J(mtFVB) strain to verify successful incorporation.
The allotopically expressed ATP8 protein in transgenic mice was constitutively expressed across all tested tissues, successfully transported into the mitochondria, and incorporated into ATP synthase. The ATP synthase with transgene had similar activity to non-transgenic control, suggesting successful integration and function. Exogenous ATP8 protein had no negative impact on measured mitochondrial function, metabolism, or behavior. Successful allotopic expression of a mitochondrially encoded protein in vivo in a mammal is a step toward utilizing allotopic expression as a gene therapy in humans to repair physiological consequences of mtDNA defects that may accumulate in congenital mitochondrial diseases or with age.
cBIN1 Gene Therapy Reverses Heart Failure
https://www.fightaging.org/archives/2024/12/cbin1-gene-therapy-reverses-heart-failure/
Progressive heart failure is at presently largely irreversible, though there is suggestive evidence for senolytic therapies to clear senescent cells from cardiac tissue to be capable of reversing at least some of its aspects, such as ventricular hypertrophy, the enlargement and weakening of heart muscle. Heart failure can arise from a combination of several underlying causes leading to some combination of structural alteration of the heart or loss of function independently of altered structure, and so there are many different classifications of heart failure based on specific outcomes.
One of the possible approaches to the treatment of age-related disease is to compensate for a specific failure, rather than trying to address its root causes. Sometimes this can be worth the effort. For example, present treatments that control blood pressure in no way address the root causes of age-related hypertension, but produce a fair-sized reduction in mortality because the raised blood pressure of hypertension is very damaging in and of itself.
In today's open access paper, researchers use a gene therapy approach to compensate for a maladaptive reduction in the expression of a gene involved in regulating heart tissue structure and function. This change in expression that occurs in the environment of heart failure is not a root cause of heart failure, just as hypertension is nowhere near the root causes of aging. It is sufficiently problematic in and of itself, however, that a compensatory therapy may be able to produce enough benefit to be worth the effort.
New Gene Therapy Reverses Heart Failure in Large Animal Model
A new gene therapy can reverse the effects of heart failure and restore heart function in a large animal model. The researchers were focused on restoring a critical heart protein called cardiac bridging integrator 1 (cBIN1). They knew that the level of cBIN1 was lower in heart failure patients - and that, the lower it was, the greater the risk of severe disease. To try and increase cBIN1 levels in cases of heart failure, the scientists turned to a harmless virus commonly used in gene therapy to deliver an extra copy of the cBIN1 gene to heart cells. They injected the virus into the bloodstream of pigs with heart failure. The virus moved through the bloodstream into the heart, where it delivered the cBIN1 gene into heart cells.
For this heart failure model, heart failure generally leads to death within a few months. But all four pigs that received the gene therapy in their heart cells survived for six months, the endpoint of the study. Importantly, the treatment didn't just prevent heart failure from worsening. Some key measures of heart function actually improved, suggesting the damaged heart was repairing itself. Previous attempted therapies for heart failure have shown improvements to heart function on the order of 5-10%. cBIN1 gene therapy improved function by 30%.
Cardiac bridging integrator 1 gene therapy rescues chronic non-ischemic heart failure in minipigs
Heart failure (HF) is a major cause of mortality and morbidity worldwide, yet with limited therapeutic options. Cardiac bridging integrator 1 (cBIN1), a cardiomyocyte transverse-tubule (t-tubule) scaffolding protein which organizes the calcium handling machinery, is transcriptionally reduced in HF and can be recovered for functional rescue in mice. Here we report that in human patients with HF with reduced ejection fraction (HFrEF), left ventricular cBIN1 levels linearly correlate with organ-level ventricular remodeling such as diastolic diameter.
Using a minipig model of right ventricular tachypacing-induced non-ischemic dilated cardiomyopathy and chronic HFrEF, we identified that a single intravenous low dose (6 × 10^11 vg/kg) of adeno associated virus 9 (AAV9)-packaged cBIN1 improves ventricular remodeling and performance, reduces pulmonary and systemic fluid retention, and increases survival in HFrEF minipigs. In cardiomyocytes, AAV9-cBIN1 restores t-tubule organization and ultrastructure in failing cardiomyocytes. In conclusion, AAV9-based cBIN1 gene therapy rescues non-ischemic HFrEF with reduced mortality in minipigs.
Transcriptional Trajectories of Aging in Nematode Worms
https://www.fightaging.org/archives/2024/12/transcriptional-trajectories-of-aging-in-nematode-worms/
What can we learn about aging from mutations that alter longevity? Rather than examining single biomarkers of aging to compare the effects of mutations, in today's open access paper the authors instead report on a comparison of the shift in all gene expression. The researchers measured the whole transcriptome across the life span of nematode worms, comparing worms with long-lived and short-lived gene variants, commenting on the results. The data supports the view that favorable gene variants literally slow aging: the same transcriptomic trajectory is observed in all worms, but stretched out over a longer period of time in the longer-lived individuals.
Is it actually helpful to examine the biochemistry underlying natural variations in life span? If the goal is to chip away at the massive undertaking of developing an complete understanding of how aging progresses at the detail level, then most likely yes. All data is useful. From the point of view of building meaningful therapies to treat aging, then most likely no. Researchers have a good map of important mechanisms in aging. The best way forward to is target those mechanisms, producing results that have no analogy in natural variations in aging. Looking at differences in how humans age will not inform us as to how good it is to entirely remove senescent cells, or entirely replace damaged mitochondria with fresh mitochondria - only actually building the therapies will answer the question of how good they are, how many years of healthy life might be added via their use.
Similarities and differences in the gene expression signatures of physiological age versus future lifespan
In contrast to chronological age, which is measured simply by the ticking of a clock, defining physiological age is a much more complex task. To deal with this complexity, we use biomarkers of aging as proxy measurements to determine how physiologically young or old an individual is. However, this requires that we understand what "young" and "old" look like for a given biomarker. Using the average biomarker levels over chronological time to build a trajectory from a youthful to aged state, we can then place an individual on this trajectory and compare whether it is physiologically older or younger than its actual chronological age would suggest. This works because biomarkers of aging vary over time in each individual at a faster or slower rate depending on each individual's rate of aging. Here, we expanded this logic by building a trajectory of aging using the whole transcriptome and comparing the transcriptomes of subpopulations predicted to be long- or short-lived by the expression of four different biomarkers of aging. In doing so, we identified a class of genes which separate along this trajectory of physiological age and another which separates orthogonally to it.
That biomarkers of aging correlate with a common physiological age state is also consistent with results suggesting that various interventions which affect population longevity, such as long-lived mutants, "rescale" lifespan and healthspan relative to the wildtype population. Researchers have shown, for instance, showed that several interventions which lengthen or shorten lifespan rescale the hazard curve of the wildtype population, and more recently it was shown that several long-lived mutants have proportionally-scaled healthspan relative to wildtype controls. Other researchers performed a meta-analysis of several RNA-seq studies of long-lived mutants and similarly found that the transcriptomic age of these populations was scaled primarily along a single axis in a manner correlated with lifespan extension. Our results suggest a similar phenomenon occurring among untreated individuals of the same population, whereby long- and short-lived individuals undergo, in large part, temporally-scaled versions of the same transcriptional trajectory. While our interpretations are limited by sorting and sequencing populations only at one time-point, future work could confirm whether differently-fated individuals continue to follow this common trajectory by sequencing at later timepoints post-sorting.
While the finding that a difference in predicted lifespan largely resembles a difference in apparent age may be intuitive, the consistency of this signature across each biomarker tested is notable. One could imagine an alternate model in which each biomarker correlates with a specific age-related etiology, resulting in several different ways to be healthy or unhealthy - instead, we find the transcriptomic differences underlying high versus low expression of each biomarker tested to be remarkably similar. This result lends further support to previous findings that certain transcriptional biomarkers of aging, even when expressed in different tissues, appear to correlate with some common underlying state related to future lifespan.
GDF-15 Expression is Induced by Inflammatory Cell Stress and Promotes Aging
https://www.fightaging.org/archives/2024/12/gdf-15-expression-is-induced-by-inflammatory-cell-stress-and-promotes-aging/
Chronic, unresolved inflammation is a feature of aging. Many of the forms of molecular damage associated with aging provoke an inflammatory response from cells, including the signaling generated by senescent cells and mitochondrial dysfunction leading to mislocalized mitochondrial DNA. Short-term inflammation is necessary for regeneration and defense against pathogens, but inflammation becomes harmful when sustained for the long term. It is disruptive to tissue structure and function, and accelerates the onset and progression of age-related conditions.
In today's open access paper, researchers note one interesting example of the way in which chronic inflammation provokes maladaptive responses. GDF-15 is an immune regulator expressed in response to inflammation, and which can dampen excessive inflammation. This is normal and beneficial in the short term. When inflammation becomes lasting, however, the constant presence of GFD-15 becomes harmful to cell function. An important goal in the treatment of aging is to find ways to suppress unwanted, chronic inflammation without suppressing necessary, transient inflammation - so far a challenge, as it appears they depend on the same pathways and systems of regulation.
GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process
The GDF15 protein, a member of the TGF-β superfamily, is a stress-induced multifunctional protein with many of its functions associated with the regulation of the immune system. GDF15 signaling provides a defence against the excessive inflammation induced by diverse stresses and tissue injuries. Given that the aging process is associated with a low-grade inflammatory state, called inflammaging, it is not surprising that the expression of GDF15 gradually increases with aging.
In fact, the GDF15 protein is a core factor secreted by senescent cells, a state called senescence-associated secretory phenotype (SASP). Many age-related stresses, e.g., mitochondrial and endoplasmic reticulum stresses as well as inflammatory, metabolic, and oxidative stresses, induce the expression of GDF15. Although GDF15 signaling is an effective anti-inflammatory modulator, there is robust evidence that it is a pro-aging factor promoting the aging process.
GDF15 signaling is not only an anti-inflammatory modulator but it is also a potent immunosuppressive enhancer in chronic inflammatory states. The GDF15 protein can stimulate immune responses either non-specifically via receptors of the TGF-β superfamily or specifically through the GFRAL/HPA/glucocorticoid pathway. GDF15 signaling stimulates the immunosuppressive network activating the functions of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages and triggering inhibitory immune checkpoint signaling in senescent cells. Immunosuppressive responses not only suppress chronic inflammatory processes but they evoke many detrimental effects in aged tissues, such as cellular senescence, fibrosis, and tissue atrophy/sarcopenia. It seems that the survival functions of GDF15 go awry in persistent inflammation thus promoting the aging process and age-related diseases.
Nutrient Processing Differences in Exhausted T Cells
https://www.fightaging.org/archives/2024/12/nutrient-processing-differences-in-exhausted-t-cells/
T cell exhaustion is a poorly defined state in which these immune cells become ineffective, less responsive to antigens. It is seen most evidently in the contexts of persistent viral infection and cancer, but exhausted T cells are also present in older people. A common theme in all of these situations is replication stress, T cells forced into greater replication in response to the circumstances they find themselves in. Replication stress also leads to greater numbers of senescent T cells, another noteworthy problem. In the context of aging replication stress occurs over time because the supply of new T cells is greatly reduced, a consequence of the atrophy of the thymus, while the body still tries to maintain the same overall population size of T cells.
At the end of the day, restoring the hematopoietic system and the thymus in order to produce a youthful supply of new T cells is probably a necessary component of any attempt to fix the issues of the aged immune system. Senescent T cells can be destroyed using senolytic drugs. But can anything be done regarding T cell exhaustion directly? In today's research materials, it is suggested that the exhausted state might be prevented or reversed by altering aspects of nutrient processing in T cells, though the best target mechanism to achieve results analogous to the genetic manipulations that postpone T cell exhaustion shown here remains to be determined.
Your immune cells are what they eat
Nutrients provide the resources for all cellular activities, but they must first be broken down into smaller molecules called metabolites. Metabolites have many uses, including promoting epigenetic regulation, a process that changes the shape of a cell's DNA to alter the accessibility of different genes. Which genes are expressed in a cell at any given time then determines the behavior and identity of the entire cell. Researchers wondered: Could this change in metabolism be responsible for the epigenetic changes that turn effector T cells into exhausted T cells? Is there a link between nutrition and exhausted T cell differentiation? One of the most important and common metabolites is acetyl-CoA, which both effector and exhausted T cells make - but with one interesting difference. Exhausted T cells tend to make their acetyl-CoA using a protein called ACLY that uses citrate, rather than using a protein called ACSS2 that uses acetate.
The preferential activity of citrate-using-ACLY in exhausted T cells and acetate-using-ACSS2 in effector T cells piqued the team's curiosity, leading them to genetically investigate the production of these metabolic proteins in both T cell subtypes. They found that ACSS2 gene expression was most highly expressed in functional T cells, but was drastically reduced in exhausted T cells in both mouse and human tissue samples. In contrast, ACLY genes were expressed similarly in both effector and exhausted T cells - with slightly greater expression in the exhausted cells. This suggested that T cells needed to express ACSS2 to maintain a functional state and that with exhaustion comes a greater reliance on ACLY.
To verify their findings, they went into the T cells and deleted ACLY and ACSS2 genes one at a time - discovering that the loss of ACLY boosted anti-tumor T cell activity, while the loss of ACSS2 did the opposite and reduced T cell efficacy. Upon closer inspection, the researchers noticed that two distinct pools of otherwise identical acetyl-CoA were piling up in different locations in the nucleus - where the cell's DNA is stored - based on whether it was derived from acetate via ACSS2 or from citrate via ACLY. Each nutrient-specific pile was then linked to unique histone acetyltransferases, which are proteins that reshape DNA and influence which genes are expressed to change cellular behavior and identity. This novel link between nutrition and cell identity offers a new explanation for exhausted T cell identity and in turn offers a multitude of new targets for future therapeutics that could keep T cells turned "on" longer.
Nutrient-driven histone code determines exhausted CD8+ T cell fates
Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.
How Might the Gut Microbiome Contribute to Heart Failure?
https://www.fightaging.org/archives/2024/12/how-might-the-gut-microbiome-contribute-to-heart-failure/
It is becoming clear that the gut microbiome plays an important role in health and aging, perhaps as influential as exercise and diet. The composition of the gut microbiome shifts in unfavorable ways with advancing age, promoting chronic inflammation and reducing the generation of beneficial metabolites. Concretely demonstrating specific mechanistic connections to specific diseases, and definitive proof for specific bacterial species to be the problem, is still a work in progress, however.
The gut microbiota (GM) plays a critical role in regulating human physiology, with dysbiosis linked to various diseases, including heart failure (HF). HF is a complex syndrome with a significant global health impact, as its incidence doubles with each decade of life, and its prevalence peaks in individuals over 80 years. A bidirectional interaction exists between GM and HF, where alterations in gut health can worsen the disease's progression.
The "gut hypothesis of HF" suggests that HF-induced changes, such as reduced intestinal perfusion and altered gut motility, negatively impact GM composition, leading to increased intestinal permeability, the release of GM-derived metabolites into the bloodstream, and systemic inflammation. This process creates a vicious cycle that further deteriorates heart function. GM-derived metabolites, including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids (BAs), can influence gene expression through epigenetic mechanisms, such as DNA methylation and histone modifications. These epigenetic changes may play a crucial role in mediating the effects of dysbiotic gut microbial metabolites, linking them to altered cardiac health and contributing to the progression of HF. This process is particularly relevant in older individuals, as the aging process itself has been associated with both dysbiosis and cumulative epigenetic alterations, intensifying the interplay between GM, epigenetic changes, and HF, and further increasing the risk of HF in the elderly.
Despite the growing body of evidence, the complex interplay between GM, epigenetic modifications, and HF remains poorly understood. The dynamic nature of epigenetics and GM, shaped by various factors such as age, diet, and lifestyle, presents significant challenges in elucidating the precise mechanisms underlying this complex relationship.
Type 2 Diabetes Makes Atherosclerosis Worse by Changing Plaque Structure
https://www.fightaging.org/archives/2024/12/type-2-diabetes-makes-atherosclerosis-worse-by-changing-plaque-structure/
Atherosclerosis is the formation of fatty plaques in blood vessel walls that grow to obstruct blood flow. The degree to which the plaque is dangers isn't just a matter of size, it is also the composition. A softer, more lipid-laden plaque is more prone to rupture, leading to a heart attack or stroke when a downstream vessel is blocked. Plaques with more fibrotic or calcified structures are less dangerous in this sense. Here, researchers provide evidence suggesting that metabolic disease makes cardiovascular disease worse by altering the structure of plaques in favor of less stability, and thus greater risk of rupture.
Type 2 diabetes is associated with cardiovascular disease, possibly due to impaired vascular fibrous repair. Yet, the mechanisms are elusive. Here, we investigate alterations in the fibrous repair processes in type 2 diabetes atherosclerotic plaque extracellular matrix by combining multi-omics from the human Carotid Plaque Imaging Project cohort and functional studies. Plaques from type 2 diabetes patients have less collagen.
Interestingly, lower levels of transforming growth factor-ß distinguish type 2 diabetes plaques and, in these patients, lower levels of fibrous repair markers are associated with cardiovascular events. Transforming growth factor-ß2 originates mostly from contractile vascular smooth muscle cells that interact with synthetic vascular smooth muscle cells in the cap, leading to collagen formation and vascular smooth muscle cell differentiation. This is regulated by free transforming growth factor-ß2 which is affected by hyperglycemia. Our findings underscore the importance of transforming growth factor-ß2-driven fibrous repair in type 2 diabetes as an area for future therapeutic strategies.
Cellular Senescence in the Context of Inducing Hair Regrowth
https://www.fightaging.org/archives/2024/12/cellular-senescence-in-the-context-of-inducing-hair-regrowth/
One of the classes of potential regenerative medicine for hair regrowth is the transplantation of cells that will provoke skin into forming new hair follicles. Dermal papilla cells are one population that might be considered in this context. Here, researchers discuss the challenge of cellular senescence in cell therapy, as it applies to dermal papilla cells and the goal of hair growth. Cultured cells will become senescent at some pace; senescent cells when transplanted may be anything from useless to actively harmful, and variation in the proportion of cultured cells that become senescent under a given protocol may be a major issue for present stem cell therapies, accounting for a wide variation in outcomes from patient to patient and clinic to clinic.
Senescent cells secrete a senescence-associated secretory phenotype (SASP), which can induce senescence in neighboring cells. Human dermal papilla (DP) cells lose their original hair inductive properties when expanded in vitro, and rapidly accumulate senescent cells in culture. Protein and RNA-seq analysis revealed an accumulation of DP-specific SASP factors including IL-6, IL-8, MCP-1, and TIMP-2. We found that combined senolytic treatment of dasatinib and quercetin depleted senescent cells, and reversed SASP accumulation and SASP-mediated repressive interactions in human DP culture, resulting in an increased Wnt-active cell population.
In hair reconstitution assays, senolytic-depleted DP cells exhibited restored hair inductive properties by regenerating de novo hair follicles (HFs) compared to untreated DP cells. In 3D skin constructs, senolytic-depleted DP cells enhanced inductive potential and hair lineage specific differentiation of keratinocytes. These data revealed that senolytic treatment of cultured human DP cells markedly increased their inductive potency in HF regeneration, providing a new rationale for clinical applications of senolytic treatment in combination with cell-based therapies.
Autoantibodies as Pathological Agents Beyond Autoimmune Conditions
https://www.fightaging.org/archives/2024/12/autoantibodies-as-pathological-agents-beyond-autoimmune-conditions/
There is the suspicion that the aging of the immune system into incapacity, inflammation, and malfunction includes a meaningful degree of low-grade autoimmunity, pathological and disruptive attacks by the immune system on the body's own structures, but not evidently rising to the level of a well-defined autoimmune condition. This is perhaps less well researched that it might be, given the many other far more evident ways in which an aged immune system becomes harmful. That the immune system does fall apart in a very complex set of ways is a strong argument for blunt approaches that involve destruction and then replacement of existing immune populations. Where this can be accomplished in a limited way in animal models, cell type by cell type, such as for microglia or for B cells, it appears to be a beneficial strategy.
Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood.
Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance.
Furthermore, the cumulative exposure to antigens and cellular debris during obesity and aging perpetuates pro-inflammatory pathways, linking immunosenescence with other aging hallmarks, such as proteostasis loss and mitochondrial dysfunction. This review examines the mechanisms driving autoantibody generation during obesity and aging and discusses key putative antigenic targets across these conditions. We also explore the therapeutic potential of emerging approaches, such as CAR-T/CAAR-T therapies, vaccines, and bispecific T cell engagers (BiTEs), to tackle autoimmune-related conditions in aging and obesity.
GDF-15 as a Biomarker of Aging
https://www.fightaging.org/archives/2024/12/gdf-15-as-a-biomarker-of-aging/
Researchers here provide evidence for circulating GDF-15 to increase with age and correlate with aging clock assessments of biological age. In the long term, more biomarkers can only help to improve our understanding of aging and the ability to measure aging sufficiently well to guide research and development to the most effective therapies. In the short term, the proliferation of interesting biomarkers is outpacing the exploration of their value. Considerable work and expense lies between where we stand now and a good understanding of how and why aging clocks work, and perhaps more importantly, how specific underlying processes of aging map to specific components of the clock measurements.
Growth differentiation factor 15 (GDF-15) has emerged as a significant biomarker of aging, linked to various physiological and pathological processes. This study investigates circulating GDF-15 levels in a cohort of healthy individuals from the Balearic Islands, exploring its associations with biological age markers, including multiple DNA methylation (DNAm) clocks, physical performance, and other age-related biomarkers. Seventy-two participants were assessed for general health, body composition, and physical function, with GDF-15 levels quantified using ELISA.
Our results indicate that GDF-15 levels significantly increase with age, particularly in individuals over 60. Strong positive correlations were observed between GDF-15 levels and DNAm GrimAge, DNAm PhenoAge, Hannum, and Zhang clocks, suggesting that GDF-15 could serve as a proxy for epigenetic aging. Additionally, GDF-15 levels were linked to markers of impaired glycemic control, systemic inflammation, and physical decline, including decreased lung function and grip strength, especially in men. These findings highlight the use of GDF-15 as a biomarker for aging and age-related functional decline. Given that GDF-15 is easier to measure than DNA methylation, it has the potential to be more readily implemented in clinical settings for broader health assessment and management.
Delivery of Platelet Factor 4 Rejuvenates Hematopoietic Stem Cell Function
https://www.fightaging.org/archives/2024/12/delivery-of-platelet-factor-4-rejuvenates-hematopoietic-stem-cell-function/
Platelet factor 4 (PF4) has been the subject of interesting research in recent years. Researchers have found that delivery of PF4 can dampen neuroinflammation in old animals and restore cognitive function. PF4 doesn't cross the blood-brain barrier to enter the brain, and the effect appears mediated by changes in the immune system. Here, researchers show that PF4 is involved in the regulation of hematopoietic stem cell function, and delivery of PF4 thus rejuvenates the generation of immune cells in aged animals. This seems promising for other strategies that also improve hematopoietic stem cell function, such as use of CASIN and derived compounds under development at Mogling Bio.
Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs.
Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
Inflammation as an Important Mechanism in the Role of Growth Hormone in Aging
https://www.fightaging.org/archives/2024/12/inflammation-as-an-important-mechanism-in-the-role-of-growth-hormone-in-aging/
Interfering in growth hormone signaling has been shown to extend life considerably in mice. Unfortunately, the analogous human populations with Laron syndrome resulting from loss of function mutations in the growth hormone receptor gene do not live notably longer than the rest of us. Thus the most important mechanisms linking growth hormone metabolism to longevity must produce smaller effects as species life span increases. Here, researchers suggest that growth hormone shortens life because it produces greater chronic inflammation in old age. Inflammation is known to drive age-related disease and mortality, which adds to the puzzle of why it is that the effects of growth hormone metabolism on life span are so small in humans versus mice.
While inflammation is a crucial response in injury repair and tissue regeneration, chronic inflammation is a prevalent feature in various chronic, non-communicable diseases such as obesity, diabetes, and cancer and in cardiovascular and neurodegenerative diseases. Long-term inflammation considerably affects disease prevalence, quality of life, and longevity. Our research indicates that the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is a pivotal regulator of inflammation in some tissues, including the hypothalamus, which is a key player in systemic metabolism regulation.
Moreover, the GH/IGF-1 axis is strongly linked to longevity, as GH- or GH receptor-deficient mice live approximately twice as long as wild-type animals and exhibit protection against aging-induced inflammation. Conversely, GH excess leads to increased neuroinflammation and reduced longevity. Our review studies the associations between the GH/IGF-1 axis, inflammation, and aging, with a particular focus on evidence suggesting that GH receptor signaling directly induces hypothalamic inflammation. This finding underscores the significant impact of changes in the GH axis on metabolism and on the predisposition to chronic, non-communicable diseases.
Nuclear Lipid Droplets as a Hallmark of Aging
https://www.fightaging.org/archives/2024/12/nuclear-lipid-droplets-as-a-hallmark-of-aging/
Abnormal localized excesses of lipids in tissues, particularly cholesterol, is a feature of aging. It is disruptive to cell function, such as via accumulation of intracellular free cholesterol when the cell's ability to safely store that cholesterol in the form of lipid droplets is overwhelmed. Cholesterol is essentially toxic in its unmodified form. Researchers here note another potential problem resulting from a local excess of lipids, which is the formation of lipid droplets in the cell nucleus rather than in the cytoplasm as is usually the case. Some work remains in order to determine exactly how this introduction of lipid droplets into the cell nucleus might cause harm, but we might hypothesize that it results in altered gene expression at the very least.
A prominent hallmark of ageing is the accumulation of dysfunctional cellular components, which disrupts tissue homeostasis, contributing to age-related pathologies. This feature includes the abnormal deposition of lipids in non-adipose tissues, known as ectopic fat, which is highly associated with metabolic syndrome and various age-related conditions, including cardiovascular disease, type 2 diabetes, and neurodegenerative disorders, among others.
Lipid droplets (LDs) are primarily recognized as cytoplasmic organelles and have a pivotal role in energy storage, lipid metabolism, and cellular homeostasis. Traditionally, LDs presence has been confined to the cytoplasm, where they serve as reservoirs of neutral lipids, supporting energy balance and membrane biosynthesis. For a long time, the association between LDs and the nucleus was under-investigated. However, recent studies have unveiled an unexpected aspect of lipid biology demonstrating that LDs can also exist within the nucleus, forming nuclear lipid droplets (nLDs).
Interventions known to extend lifespan, such as caloric restriction and reduced insulin signaling, significantly reduce both the rate of accumulation and the size of nLDs. The triglyceride lipase ATGL-1, which localizes to the nuclear envelope, plays a critical role in limiting nLD buildup and maintaining nuclear lipid balance, especially in long-lived mutant nematode worms. These findings establish excessive nuclear lipid deposition as a key hallmark of aging, with profound implications for nuclear processes such as chromatin organization, DNA repair, and gene regulation. In addition, ATGL-1 emerges as a promising therapeutic target for preserving nuclear health, extending organismal healthspan, and combating age-related disorders driven by lipid dysregulation.
Thoughts on the Hallmarks of Aging in Comparative Biology
https://www.fightaging.org/archives/2024/12/thoughts-on-the-hallmarks-of-aging-in-comparative-biology/
The comparative biology of aging, using species with radically different life courses as a way to identify important mechanisms in the progression of aging, is an interesting area of research. Why do naked mole rats live nine times longer than mice? Why do whales live so much longer than humans? What are the largest determinants of species life span? And so forth. It remains to be seen as to whether potential therapies can be made in a reasonable span of time and effort by mining the biochemistry of long-lived species, but the real goal of the scientific community has always been understanding, not intervention. Here, researchers comment on the relevance of the hallmarks of aging to research into aging in different species, particularly those in which aging progresses very differently than is the case in mice and humans.
Since the first description of a set of characteristics of aging as so-called hallmarks or pillars in 2013/2014, these characteristics have served as guideposts for the research in aging biology. They have been examined in a range of contexts, across tissues, in response to disease conditions or environmental factors, and served as a benchmark for various anti-aging interventions. While the hallmarks of aging were intended to capture generalizable characteristics of aging, they are derived mostly from studies of rodents and humans. Comparative studies of aging including species from across the animal tree of life have great promise to reveal new insights into the mechanistic foundations of aging, as there is a great diversity in lifespan and age-associated physiological changes. However, it is unclear how well the defined hallmarks of aging apply across diverse species.
Here, we review each of the twelve hallmarks of aging defined in 2023 with respect to the availability of data from diverse species. We evaluate the current methods used to assess these hallmarks for their potential to be adapted for comparative studies. Not unexpectedly, we find that the data supporting the described hallmarks of aging are restricted mostly to humans and a few model systems and that no data are available for many animal clades. Similarly, not all hallmarks can be easily assessed in diverse species. However, for at least half of the hallmarks, there are methods available today that can be employed to fill this gap in knowledge, suggesting that these studies can be prioritized while methods are developed for comparative study of the remaining hallmarks.
Visceral Fat Correlates with the Burden of Amyloid and Tau in the Aging Brain
https://www.fightaging.org/archives/2024/12/visceral-fat-correlates-with-the-burden-of-amyloid-and-tau-in-the-aging-brain/
Researchers here report that the amount of visceral fat carried by an individual correlates with the burden of Alzheimer's-related pathological protein aggregation in the brains of people in middle age prior to the development of any neurodegenerative condition. It is at this point well known that visceral fat specifically is metabolically active, promoting chronic inflammation and in at least some aspects literally accelerating aging. The study population was largely obese, so this study tells us little regarding whether this relationship extends into much lesser degrees of being overweight. Past data has suggested that any amount of excess visceral fat tissue produces dysfunction, scaling up with the size of the excess, however.
Researchers focused on the link between modifiable lifestyle-related factors, such as obesity, body fat distribution and metabolic aspects, and Alzheimer's disease pathology. A total of 80 cognitively normal midlife individuals (average age: 49.4 years) were included in the study. Approximately 57.5% of participants were obese, and the average body mass index (BMI) of the participants was 32.31. The participants underwent brain positron emission tomography (PET), body MRI, and metabolic assessment (glucose and insulin measurements), as well as a lipid (cholesterol) panel. MRI scans of the abdomen were performed to measure the volume of the subcutaneous fat (the fat under skin) and visceral fat (deep hidden fat surrounding the organs). Thigh muscle scans were used to measure volume of muscle and fat. Alzheimer's disease pathology was measured using PET scans with tracers that bind to amyloid plaques and tau tangles that accumulate in the brains of people with Alzheimer's disease.
Our study showed that higher visceral fat was associated with higher PET levels of the two hallmark pathologic proteins of Alzheimer's disease - amyloid and tau. To our knowledge, our study is the only one to demonstrate these findings at midlife where our participants are decades out from developing the earliest symptoms of the dementia that results from Alzheimer's disease." The study also showed that higher insulin resistance and lower HDL were associated with high amyloid in the brain. The effects of visceral fat on amyloid pathology were partially reduced in people with higher HDL.
View the full article at FightAging
