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Contents
- Progerin Acts in Normal Aging as well as Progeria, but is it Important?
- Lymph Node Organoids Integrate into the Lymphatic System and Restore Function
- Understanding Why the Immune System Fails to Destroy Lingering Senescent Cells May Lead to New Senolytic Therapies
- Declining Microcirculation as an Important Aspect of Aging
- Cellular Senescence as a Program of the Innate Immune System
- Blocking Translation of α-synuclein RNA to Treat Parkinson's Disease
- Reviewing the Biochemistry of Survival in Senescent Cells
- Mast Cells in Age-Related Neurodegeneration and Neuroinflammation
- A Natural Mechanism that Breaks Down α-Synuclein Aggregates
- Extremely Long Lived Cells are Found in Many Tissues, Not Just the Brain
- Cellular Antioxidant Defenses Measured in Blood Samples Decline with Age
- Towards Bioprinted Corneas
- The Contribution of Reactive Astrocytes to Neurodegeneration
- People Remain Hopeful that Something Useful can be Accomplished with Minoxidil
- Talking with Laura Deming: Aging is the World's Most Important Problem
Progerin Acts in Normal Aging as well as Progeria, but is it Important?
https://www.fightagi...s-it-important/
Hutchinson-Gilford Progeria Syndrome, or just progeria, results from the production of a broken protein progerin from the Lamin A gene. The functional form of Lamin A is vital to the structure of cells, and without it cellular damage and tissue dysfunction rapidly accrue. This results in a short lifespan with a superficial resemblance to accelerated aging. It is not accelerated aging, however: aging is a specific mix of forms of cell tissue damage and consequent dysfunction, and progeria is a radically different mix. Where there are similar outcomes, it is because some tissues will tend to fail in similar ways regardless of the specific cause of underlying cellular dysfunction.
While progeria results from the rare occurrence of mutation in the Lamin A gene, in recent years the presence of progerin at low levels has been observed in old individuals undergoing normal aging. This appears to be associated with cellular senescence, with progerin production being, for reasons yet to be fully understood, a feature of senescent cells. Even in very late life only a small fraction of cells in any given tissue are senescent, accounting for the overall low level of progerin, but senescent cells inflict an outsized level of harm on tissue function via a potent inflammatory mix of secreted proteins.
When we ask whether progerin is important in natural aging, this may just boil down to whether or not it is doing anything beyond participating in some way in the biochemistry of senescent cells. If it is just another portion of the internal mechanisms of cellular senescence, then it will not be necessary to tackle it as a distinct mechanism. The dominant approach to senescent cells in aged tissue is to selectively destroy them: no more senescent cells, no more progerin. Alternatively, are normal cells in aged tissues falling into a state in which they produce enough progerin in order to become senescent? Even in this case we may still be able to ignore this mechanism for practical purposes, given efficient enough senolytic treatments to clear out senescent cells every so often.
Are There Common Mechanisms Between the Hutchinson-Gilford Progeria Syndrome and Natural Aging?
The Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by mutations of the LMNA gene leading to increased production of a partially processed form of the protein lamin A - progerin. Progerin acts as a dominant factor that leads to multiple morphological anomalies of cell nuclei and disturbances in heterochromatin organization, mitosis, DNA replication and repair, and gene transcription.
Progerin-positive cells are present in primary fibroblast cultures obtained from the skin of normal donors at advanced ages. These cells display HGPS-like defects in nuclear morphology, decreased H3K9me3 and HP1, and increased histone H2AX phosphorylation marks of the DNA damage loci. Inhibition of progerin production in cells of aged non-HGPS donors in vivo increases the proliferative activity, H3K9me3, and HP1, and decreases the senescence markers p21, IGFBP3, and GADD45B to the levels of young donor cells. Thus, progerin-dependent mechanisms act in natural aging. Excessive activity of the same mechanisms may well be the cause of premature aging in HGPS.
Telomere attrition is widely regarded to be one of the primary hallmarks of aging. Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. The chronological aging in normal individuals and the premature aging in HGPS patients are mediated by similar changes in the activity of signaling pathways, including downregulation of DNA repair and chromatin organization, and upregulation of ERK, mTOR, GH-IGF1, MAPK, TGFβ, and mitochondrial dysfunction. Multiple epigenetic changes are common to premature aging in HGPS and natural aging. Recent studies showed that epigenetic systems could play an active role as drivers of both forms of aging. It may be suggested that these systems translate the effects of various internal and external factors into universal molecular hallmarks, largely common between natural and accelerated forms of aging.
Drugs acting at both natural aging and HGPS are likely to exist. For example, vitamin D3 reduces the progerin production and alleviates most HGPS features, and also slows down epigenetic aging in overweight and obese non-HGPS individuals with suboptimal vitamin D status.
Lymph Node Organoids Integrate into the Lymphatic System and Restore Function
https://www.fightagi...store-function/
The lymphatic system is vital to the correct operation of the immune response: lymph nodes are where immune cells communicate with one another in order to direct the response to invading pathogens and other threats. Unfortunately lymph nodes deteriorate with age, becoming inflammatory and fibrotic, no longer able to host the necessary passage and communication of immune cells. Researchers have demonstrated that, at least in late life, this can prevent improvements elsewhere in the aged immune system from producing the expected benefits in the immune response. What use extra immune cells or better immune cells if those cells cannot coordinate correctly? There are signs that lymph node degeneration may be due in part to the presence of senescent cells, in which case we might hope that senolytic therapies will help, but this has yet to be assessed by the research community.
What if new lymph nodes can be provided, however? Today's open access paper is a report on the generation and transplantation of organoids capable of functioning as lymph nodes. In mice, transplanted organoids can integrate with the lymphatic system and begin to perform the duties of lymph nodes. While these were not aged mice, and the transplanted organoids replaced lymph nodes that had been surgically removed, rather than augmenting those damaged by aging, this is still promising. This line of research could become one of the suite of approaches that will needed to restore the immune system of an older individual to full, youthful function.
The other necessary therapies for immune rejuvenation are: regrowth of the thymus, responsible for maturation of T cells of the adaptive immune system, and which atrophies with age; rejuvenation of the hematopoietic stem cell population in the bone marrow, source of all immune cells, and damaged and diminished in older individuals; and clearance of the senescent, exhausted, misconfigured, and otherwise broken or inappropriate immune cells that come to clutter up the immune system in late life. A few different approaches for each of these line items are at various stages of development. Given a the timescale of a decade or two we should be optimistic that the effects of aging on the immune system can be significantly reversed.
Therapeutic Regeneration of Lymphatic and Immune Cell Functions upon Lympho-organoid Transplantation
Lymph node (LN) development is a multistep process involving crosstalk of multiple cell types and culminating in integration of LNs into the lymphatic system. Non-hematopoietic stromal progenitors of lymphoid organs play critical roles in tissue development, organization, and function through the secretion of cytokines, chemokines, and the extracellular matrix (ECM), a tri-dimensional scaffold that provides structural support and anchorage for cells. Afferent-collecting lymphatics transport lymph and antigens to the LN where immune responses are generated. However, surgical resection of LNs, radiation therapy, or infections may damage the lymphatic vasculature and contribute to secondary lymphedema, a chronic disease characterized by excessive tissue swelling, fibrosis, and decreased immune responses.
Currently available lymphedema treatments are limited to manual lymph drainage and compression garments, and definitive therapeutic options are still lacking. Vascularized autologous lymph node transfer (ALNT), a surgical procedure in which a LN flap is harvested and transplanted at the site of resected LNs to improve lymphatic drainage, is emerging as a therapeutic option for the treatment of cancer-associated lymphedema. Although feasible, such an approach requires surgical intervention and can be associated with donor-site complications, which may limit its application.
To circumvent these problems, tissue engineering may provide strategies to develop artificial lymphoid tissues for applications in regenerative medicine. It has been demonstrated that transplantation under the kidney capsule of an engineered stromal cell line expressing lymphotoxin α in a biocompatible scaffold or the delivery of stromal-derived chemokines in hydrogel is sufficient to promote the organization of lymphoid-like structures with immunological function. Whether these approaches contribute to regenerate immune and lymphatic functions in preclinical models of LN resection remains unknown.
Here, we generated lympho-organoids (LOs) using LN stromal progenitors in an ECM-based scaffold and show that LO transplantation at the site of resected LN contributes to restoration of lymphatic and immune functions. Upon transplantation, LOs are integrated into the endogenous lymphatic vasculature and efficiently restore lymphatic drainage and perfusion. Notably, upon immunization, LOs support the activation of antigen-specific immune responses and acquire properties of native lymphoid tissues. These findings provide a robust preclinical approach for the development of synthetic LOs capable of regenerating lymphatic and immune functions.
Understanding Why the Immune System Fails to Destroy Lingering Senescent Cells May Lead to New Senolytic Therapies
https://www.fightagi...ytic-therapies/
The accumulation of lingering senescent cells in all tissues is one of the causes of aging. Even in very late life, senescent cells are thought to account for only a few percent at most of all cells in any given tissue, but they cause great disruption to tissue structure and function: chronic inflammation, impaired regeneration, fibrosis, and other unpleasant outcomes. This is accomplished via an as yet incompletely cataloged mix of secreted molecules known as the senescence-associated secretory phenotype, or SASP. Acting via secretions allows a small number of cells to have large effects.
When present for a limited period of time, senescent cells are helpful, a necessary part of wound healing, embryonic development, and suppression of cancer. Cells become senescent in response to the circumstance, the SASP assists in calling in the immune system to help, or in spurring growth, or in instructing nearby cells to also become senescent. Then the senescent cells self-destruct or are destroyed by the immune system once their contribution to the task at hand is complete. It is only when senescent cells linger for the long term that the SASP becomes dangerous, corrosive to tissue function.
Why do some senescent cells fail to self-destruct? Further, while we know that the immune system declines with age, becoming less effective in all of its tasks, why specifically do immune cells fail to identify and destroy some senescent cells? Progress towards more complete and detailed answers these questions may open the door to new classes of senolytic therapy, capable of purging senescent cells from old tissues. While a variety of senolytic treatments are either available or under development, none are capable of destroying more than about half at best of these cells, and then only in some tissues. Combinations of different therapies, and more efficient therapies will be needed in the years ahead.
Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition
Cellular senescence is an evolutionarily conserved mechanism with beneficial effects on tumour suppression, wound healing and tissue regeneration. During ageing, however, senescent cells accumulate in tissues and manifest deleterious effects, as they secrete numerous pro-inflammatory mediators as part of a senescence-associated secretory phenotype (SASP). The elimination of senescent cells in mouse models was shown sufficient to delay the onset or severity of several age-related phenotypes. This has prompted the development of senolytic drugs that selectively target senescent cells. Despite successful reversal of age-related pathologies in animal models, the use of senolytic drugs in humans may be hampered by their lack of specificity for senescent cells, leading to the risk of toxicity. Therefore, alternative approaches that can be used in isolation or in combination with senolytic drugs to improve the elimination of senescent cells in humans should be explored.
Senescent cells can be recognised and eliminated by the immune system. Different immune cell types including macrophages, neutrophils, natural killer (NK) cells and CD4+ T cells have been implicated in the surveillance of senescent cells, depending on the pathophysiological contex. Senescent cells become immunogenic by expressing stimulatory ligands like MICA/MICB that bind to NKG2D and activate their killing by NK cells. Moreover, by secreting chemokines and cytokines, senescent cells can recruit immune cells into tissues that enable senescent cell clearance. However, this secretory process may perpetuate a low-level chronic inflammatory state that underlies many age-related diseases.
Despite the evidence for senescent cell clearance by the immune system, it is not yet clear why senescent cells accumulate during ageing and persist at sites of age-related pathologies. A decline in immune function may contribute to incomplete elimination of senescent cells with age. Ageing has a great impact in both innate and adaptive immune systems, a process known as immunosenescence. Alternatively, changes in major histocompatibility complex (MHC) expression can lead to escape from recognition by the immune system as previously described in cancer and virally infected cells in vivo. Nevertheless, the effects of senescence on MHC expression are not fully understood.
Here, we show that senescent primary human dermal fibroblasts express increased levels of the non-classical MHC-class Ib molecule HLA-E. HLA-E inhibits immune responses against senescent cells by interacting with the inhibitory receptor NKG2A expressed on NK and highly differentiated CD8+ T cells. Accordingly, we find an increased frequency of HLA-E expressing senescent cells in the skin of old compared with young subjects. HLA-E expression is induced by SASP-related pro-inflammatory cytokines, in particular IL-6 and regulated by p38 signalling in vitro. Lastly, we show that that blocking HLA-E/NKG2A interactions in cell culture enhances NK and CD8+ T cell-mediated cytotoxicity against senescent cells. Taken together, these findings suggest that HLA-E expression contributes to the persistence of senescent cells in tissues. HLA-E may therefore represent a novel target for the therapeutic elimination of senescent cells in age-related diseases.
Declining Microcirculation as an Important Aspect of Aging
https://www.fightagi...spect-of-aging/
Tissues are supported by dense and intricate networks of capillaries, hundreds passing through any square millimeter cross-section. Many studies have shown that capillary density decreases with age, which is perhaps another of the many results of faltering tissue maintenance due to the decline in stem cell activity, or alternatively, a specific dysregulation of the processes of angiogenesis at the small scale, resulting from inappropriate cellular reactions to rising levels of damage and chronic inflammation. Fewer capillaries means a lesser delivery of nutrients and oxygen, and we might well wonder to what degree this contributes to atrophy and dysfunction in energy hungry tissues such as muscles and the brain.
In this context, consider of the loss of muscle mass and strength that occurs with aging, known as sarcopenia. While sarcopenia is associated with a long, long list of potential contributing mechanisms, arguably the best evidence suggests that this loss of muscle capacity is caused by the declining activity of muscle stem cell populations. This connects well with a decline in capillary density, in that we can theorize either side as cause or consequence of the other. Another possible contributing factor is age-related mitochondrial dysfunction. Given that mitochondria are the power plants of the cell, responsible for transforming energy from nutrients into a form that cells can use, here too the possible connections to declining capillary density are obvious.
The two different approaches to this challenge are quite different. On the one hand, the first and more mainstream approach would be to attempt to override changes in the regulation of angiogenesis, forcing different expression levels in various regulatory proteins in order to generate greater generation of blood vessels. This strategy can produce benefits, but because it fails to address the underlying causes, the benefits are necessarily limited. The damage of aging marches on, causing all of its other consequences. One might look at past efforts to control raised blood pressure or chronic inflammation to see the plausible beneficial outcomes that can emerge from tackling important facets of aging in ways that do not repair the causes. The second, and as yet less popular - but better! - approach is to repair the damage that causes aging, and thus remove the dysregulation in angiogenesis and tissue maintenance that way. Sadly, this path forward is nowhere near as popular and well funded as it should be.
A Microcirculatory Theory of Aging
The term "microcirculation" in contrast with macrocirculation (which is the flow of blood to and from organs), refers to a network of terminal vessels comprising arterioles, capillaries and venules that are less than 100 μm in diameter. In other words, the microcirculation is defined as the blood flow through the smallest vessels in the vasculature and are embedded within organs and tissues, which facilitate the exchange of biological material between the blood and tissue via its large surface area and low blood velocity in these regions. For organs to function well, there must be sufficient perfusion throughout the tissue in the form of intact and appropriate microcirculatory vascularization.
There is a substantial number of studies presenting strong evidence of decreased vessel density with age, indicating an age-associated failure of vascular recovery in organs such as the brain in animals and humans alike. In studies involving aged rodents: healthy senescent rats (29 months) experienced a loss of about 40% of arteriolar density on the cortical surface compared with young adult rats (13 months). In the hippocampus of aged rats, there was a 20% decrease in capillary number, 3% decrease in capillary length, and 24% increase in intercapillary distance. Comparable reductions could also be found in other brain regions including the brain stem, cortex, and white matter. In studies involving aged humans: Capillary density decreased by 16% in the calcarine cortex while vascular density decreased by 50% in the paraventricular nucleus, frontal cortex, and putamen. Importantly, angiogenesis has been found to be impaired in aged tissues, which could contribute to the significant decreases in vascular density and number that has been reported.
Factors of vascular aging are reported to be closely associated with chronological age. Indeed, alterations in vascular mechanics and structure are related with vascular aging, resulting in less elastic arteries and diminished arterial compliance. Furthermore, the increased diffusion distance for oxygen caused by reduced capillary numbers and density, gives rise to heterogeneous perfusion, where the close proximity of perfused capillaries and non-perfused capillaries triggers alterations to oxygen extraction even when blood flow to the tissue is conserved.
Under normal physiological conditions, the microcirculatory blood flow is adapted to the metabolic levels of human tissues and organs, so the physiological functions of various organs in the human body can function as they should. Once the microcirculation of the human body is impaired, cells would not be able to get enough nutrition and oxygen, and meanwhile, CO2 and metabolic products, including those that are toxic, cannot be removed and will accumulate. Consequently, deterioration of physiological functions of cells and then organs that are necessary for survival and reproduction will occur. Microcirculatory impairment arises in adulthood and becomes progressively impaired with aging; the corresponding tissue system or internal organs are affected and unable to function normally, which eventually lead to aging. Therefore, aging is the process of continuous impairment of microcirculation in the body.
Cellular Senescence as a Program of the Innate Immune System
https://www.fightagi...-immune-system/
The authors of today's open access research offer an interesting viewpoint on cellular senescence in the context of cancer, presenting it as an aspect of the innate immune response to the signs of cancer-inducing mutational damage, or to the signs of cancer suppression programs operating in cells. The objective of the body's numerous, layered defenses against cancer is to destroy all cells that show the signs of becoming cancerous. The first line of defense is the state of cellular senescence, in which cells shut down their ability to replicate, prime themselves to self-destruct via the programmed cell death path of apoptosis, and alert the immune system via a mix of inflammatory secretions known as the senescence-associated secretory phenotype (SASP). These secretions also raise the odds of other surrounding cells becoming senescent, which in theory helps to stay ahead of the replication of an early cancer.
Cellular senescence in this context of cancer is likely an adaptation of an existing tool. Transient cellular senescence occurs during embryonic growth and wound healing, a way to help guide structure and regeneration. That it can also help to shut down early stage cancer has the look of a later development. Unfortunately cellular senescence is an imperfect tool: senescent cells are not reliably removed by the immune system, and they do not reliably self-destruct. Some tiny fraction linger, and their continued inflammatory secretions are an important contributing cause of aging and age-related disease.
In recent years, the research community has found ways to selectively destroy a fraction of the senescent cells present in old tissues. This approach to the treatment of aging reliably extends life span and reverses numerous age-related diseases in mice. Numerous companies are working on ways to destroy senescent cells, and the first therapies are entering human trials. Meanwhile, ever more funding is flowing towards fundamental research into the biochemistry of senescence, as there are likely many more potential approaches to the destruction or management of senescent cells yet to be discovered. This point is illustrated well in the open access paper here, as the authors propose a new point of intervention based on their research.
The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype
We describe here an essential innate immune signaling pathway in oncogene-induced senescence (OIS) established between TLR2 and acute-phase serum amyloid A1 and serum amyloid A2 (A-SAAs) that initiates the senescence-associated secretory phenotype (SASP) and reinforce cellular senescence in vitro and in vivo. We also identify new important SASP components, A-SAAs, which are the senescence-associated damage-associated molecular patterns (DAMPs) sensed by TLR2 after oncogenic stress. Therefore, we are reporting that innate immune sensing is critical in senescence. We propose that cellular senescence shares mechanistic features with the activation of innate immune cells and could be considered a program of the innate immune response by which somatic cells switch their regular role to acquire an immune function under certain conditions of stress and danger, for instance, upon oncogene activation.
Besides revealing a role for TLR2 in SASP induction and cell cycle regulation, we identified the DAMP that activates TLR2 in OIS. Acute-phase proteins SAA1 and SAA2 act to prime the TLR2-mediated inflammasome, and in turn, their full induction depends on TLR2 function. Hence, they establish a foundational feedback loop that controls the SASP. A-SAAs are systemically produced in the liver and released into the bloodstream during an acute inflammatory response. Our identification of these molecules as mediators of senescence suggests that systemic elevation of A-SAAs might have an impact on the accumulation of senescent cells and the activation of their proinflammatory program at the organismal level.
We found activation of TLR2 expression in parallel to A-SAAs in models of OIS in mice, in inflammation-induced senescence, in aging, and in different in vitro systems of senescence. Also, we have shown that TLR2 controls the activation of the SASP and OIS in vivo. Moreover, we have observed a dose-dependent effect for TLR2 in A-SAA sensing and a role for TLR2 in SASP activation during paracrine senescence. Together, these data suggest that systemic A-SAA elevation during acute inflammation could affect cells expressing TLR2, thereby promoting aging and other pathological roles of senescence. Further investigation may reveal additional physiological circumstances under which senescence is induced or reinforced by the interaction of TLR2 with A-SAAs or indeed with other endogenous DAMPs or exogenous pathogen-associated molecular patterns (PAMPs) from the microbiome. These circumstances could have implications for organismal well-being, in particular, the development of aging and cancer.
In recent years, several strategies have been implemented to eliminate senescent cells or to modulate the activation of the SASP in anti-aging and cancer therapies (senotherapies). For example, genetic targeting for the elimination of senescent cells can delay organismal aging and aging-associated disorders. Furthermore, the pharmacological suppression of the SASP has been shown to improve homeostasis in tissue damage and aging. However, most of these manipulations are directed to essential homeostatic regulators such as mTOR or crucial proinflammatory mediators such as IL-1 signaling. Here, we propose the alternative of manipulating A-SAA-TLR2 as a new rationale for senotherapies aiming to manipulate nonessential and senescence-specific signaling pathways.
Blocking Translation of α-synuclein RNA to Treat Parkinson's Disease
https://www.fightagi...insons-disease/
Parkinson's disease is a synucleinopathy, meaning that its pathology, the damage done to the brain, is driven at least in part by the aggregation of α-synuclein. Effective means to clear out α-synuclein and other protein aggregates from the aging brain, such as those resulting from amyloid-β and tau, are likely to form the basis of the first truly effective treatments for a range of neurodegenerative conditions. Though, as the Alzheimer's research community has demonstrated over the past twenty years, this is easier said than done. Little more than vast expense and failed human trials have thus far resulted from the development of immunotherapies to target the removal of amyloid-β. Success is elusive in that part of the field. Now, however, the research community is diversifying its efforts, with many groups seeking radically different approaches to the challenge of protein aggregation. Some will eventually succeed.
The exact cause of Parkinson's disease (PD) is still a mystery, but researchers believe that both genetics and the environment are likely to play a part. Importantly though, all PD patients show a loss of dopaminergic neurons in the brain and increased levels of a protein called α-synuclein, which accumulates in Lewy bodies. Lewy bodies are a pathological feature of the disease, as well as some types of dementia.
In a study published this month, researchers focused on α-synuclein as a target for a novel PD treatment. "Although there are drugs that treat the symptoms associated with PD, there is no fundamental treatment to control the onset and progression of the disease. Therefore, we looked at ways to prevent the expression of α-synuclein and effectively eliminate the physiological cause of PD."
To do this, the researchers designed short fragments of DNA that are mirror images of sections of the α-synuclein gene product. The constructs were stabilized by the addition of amido-bridging. The resulting fragments, called amido-bridged nucleic acid-modified antisense oligonucleotides (ASOs), bind to their matching mRNA sequence, preventing it from being translated into protein. After screening 50 different ASOs, the researchers settled on a 15-nucleotide sequence that decreased α-synuclein mRNA levels by 81%. "When we tested the ASO in a mouse model of PD, we found that it was delivered to the brain without the need for chemical carriers. Further testing showed that the ASO effectively decreased α-synuclein production in the mice and significantly reduced the severity of disease symptoms within 27 days of administration."
Reviewing the Biochemistry of Survival in Senescent Cells
https://www.fightagi...enescent-cells/
Now that senescent cells are conclusively demonstrated to be highly influential in the progression of degenerative aging, and broad reversal of aspects of aging is regularly demonstrated in mice via the use of various senolytic therapies, there is considerably more interest and funding in the research community for investigations of the fundamental biochemistry of senescent cells. Senescent cells are generated constantly in all tissues, and are primed for self-destruction via apoptosis. The vast majority either self-destruct or are destroyed by the immune system, quite soon after their creation. Those that linger in tissues to cause aging and age-related disease are in some way resistant to apoptosis, and the mechanisms involved in that resistance are of great relevance to the development of future senolytic therapies, treatments capable of selectively destroying senescent cells.
Increasing evidence suggests that senescent cells are primed to apoptosis due to unresolved chronic stresses, and this might favor the efficacy of known senolytic drugs. In oncology, two-step therapeutic strategies aim to first induce cancer cells into senescence via cytotoxic drugs and then to exploit the vulnerability of senescent cancer cells to apoptosis by using senolytics. However, given the deleterious roles of senescent cells, and the negative systemic side effects associated to chemotherapy, these strategies should be best approached with caution. Recently, the use of genetic screens and compound libraries has yielded aurora kinase inhibitors as powerful inducers of senescence in cancer cells (independent of p53). Importantly, senescent cancer cells also acquired vulnerability to the anti-apoptotic Bcl-2 inhibitor ABT-263 regardless of how senescence was induced. Further research is needed to assess the effects of aurora kinase inhibition in normal cells, as opposed to chemotherapy, in combination with senolytic drugs.
Redundant mechanisms aid cell death prevention in both senescent and cancer cells, as observed with anti-apoptotic Bcl-2 family homologs. Nevertheless, as senescent cells may rely more on anti-apoptotic players compared to normal cells that are free of intracellular stressors, targeting anti-apoptotic players may still represent a viable therapeutic strategy. Moreover, different apoptotic mechanisms exist across different cell types and senescent programs, and these differences may be exploited to allow preferential elimination of a specific subtype of senescent cells. In this respect, targeting a defined senescent subtype that is relevant to a specific pathology may be more desirable and with less side effects than simultaneously targeting all types of senescent cells.
It is important to note that senescent cells rely on multiple levels of regulation in order to achieve apoptosis resistance. The concurrent targeting of multiple and indirectly related anti-apoptotic pathways (SCAPs) may therefore result in increased sensitivity of senescent cells without incurring in toxicities for normal proliferating or quiescent cells. A combinatorial approach to senescent cell clearance is exemplified by the concomitant treatment of dasatinib and quercetin. Targeting SCAP networks, as opposed to single targets, may enable lowering the therapeutic dosage of each drug, therefore decreasing off- and on-target side effects associated to single drugs.
Despite an increased resistance to certain apoptotic stimuli, senescent cells may be more susceptible to various forms of metabolic targeting. Senescent cell hypercatabolism can be pharmacologically exploited for the elimination of senescent cells by means of synthetic lethal approaches such as glycolysis inhibition, autophagy inhibition, and mitochondrial targeting. Synthetic lethal metabolic targeting could therefore be used alone or in combination with SCAP inhibitors for increased selectivity.
Finally, additional strategies alternative to apoptosis induction may be employed to alleviate the deleterious phenotypes associated to senescent cells. For instance, the use of SASP modulators may prevent the establishment of a chronic SASP and dampen the negative side-effects of senescent cell persistence without the need for their removal from tissues. Similarly, the use of selective inhibitors for specific SASP components, such as neutralizing antibodies, may allow a tailoring of the SASP by only targeting SASP components thought to play a negative role in the tissue micro-environment while preserving the beneficial ones. Lastly, enhancing the natural clearance of senescent cells by the immune system could be another way of overcoming apoptosis resistance. The use of immune modulators or artificially increasing the number of immune effector cells may effectively restore senescence surveillance, and decrease the senescent cell burden.
Mast Cells in Age-Related Neurodegeneration and Neuroinflammation
https://www.fightagi...roinflammation/
Of late, it is becoming clear that the dysfunction of immune cells of the central nervous system, such as microglia, is an important part of neurodegeneration. Growing degrees of cellular senescence in these cell populations, leading to inflammatory signaling, appears to be significant in the progression of Alzheimer's disease, for example. There are many distinct types of supporting cell in the brain, however. This short open access review paper discusses the evidence for dysfunction of the immune cells known as mast cells to be relevant to the progression of chronic inflammation and neurodegeneration in the aging brain.
Mast cells are "first responders" that become activated with exposure to a diverse array of stimuli, from allergens and antigens to neuropeptides, trauma, and drugs. Activated mast cells are multifunctional effector cells that exert a variety of both immediate and delayed actions.
Neuroinflammation, which is now recognized as a primary pathological component of diseases such as multiple sclerosis, is gaining acceptance as an underlying component of most, if not all, neurodegenerative diseases. Whereas past focus has predominantly centered on glial cells of the central nervous system, recently mast cells have emerged as potential key players in both neuroinflammation and neurodegenerative diseases. Mast cells are well positioned for such a role owing to their ability to affect both their microenvironment and neighboring cells including T cells, astrocytes, microglia, and neurons. The secretory granules of mast cells contain an arsenal of preformed/stored immunomodulators, neuromodulators, proteases, amines, and growth factors that enable complex cross-communication, which can be both unidirectional and bidirectional. Mast cells can also affect disruption/permeabilization of the blood-brain barrier and this has the potential for dramatically altering the neuroinflammatory state.
With respect to Alzheimer's disease (AD), Parkinson's disease (PD), ALS, and Huntington's disease (HD), mast cell perturbation of the blood-brain barrier appears to share a commonality. Moreover, mast cells have been found to home to sites of amyloid deposition in AD; and, an inhibitor of mast cell function was shown to reduce cognitive decline in AD patients. Mast cell interactions with neurons and glial cells have also been implicated in PD pathogenesis. Emerging evidence suggests that mast cell autocrine signaling may contribute to ALS: The mast cell chemoattractant, IL-15, is elevated in the serum and cerebrospinal fluid of ALS patients; and, mast cells expressing IL-17 have been found in the spinal cord of ALS patients. Plasma levels of cytokines (IL-6, IL-8), known to affect mast cell activation, have been correlated with functional scores in HD patients suggesting the possible involvement of mast cells in the pathogenesis of HD.
A Natural Mechanism that Breaks Down α-Synuclein Aggregates
https://www.fightagi...ein-aggregates/
The brain exhibits a range of natural mechanisms for the clearance of various protein aggregates involved in neurodegenerative disease, both inside and outside the cells: clearance via immune cells; autophagy within cells; carried away via drainage of cerebrospinal fluid; and so forth. Clearly these mechanisms falter and become overwhelmed with advancing age, an outcome that results from a progressively increased burden of cell and tissue damage. Where a natural repair and maintenance mechanism exists, looking for ways to enhance that mechanism is one of the logical places to make a start on the development of viable therapies.
Aggregates of the protein alpha-synuclein in the nerve cells of the brain play a key role in Parkinson's and other neurodegenerative diseases. These protein clumps can travel from nerve cell to nerve cell, causing the disease to progress. Relevant for these diseases are long but yet microscopic fibres, or fibrils, to which large numbers of the alpha-synuclein molecules can aggregate. Individual, non-aggregated alpha-synuclein molecules, however, are key to the functioning of a healthy brain, as this protein plays a key role in the release of the neurotransmitter dopamine in nerve cell synapses.
When the protein aggregates into fibrils in a person's nerve cells - before which it must first change its three-dimensional shape - it can no longer carry out its normal function. The fibrils are also toxic to the nerve cells. In turn, dopamine-producing cells die, leaving the brain undersupplied with dopamine, which leads to typical Parkinson's clinical symptoms such as muscle tremors. "Once the fibrils enter a new cell, they 'recruit' other alpha-synuclein molecules there, which then change their shape and aggregate together. This is how the fibrils are thought to infect cells one by one and, over time, take over entire regions of the brain."
Researchers were able to decipher a cellular mechanism that breaks down alpha-synuclein fibrils naturally. A protein complex called SCF detects the alpha-synuclein fibrils specifically and targets them to a known cellular breakdown mechanism. In this way, the spread of fibrils is blocked, as the researchers demonstrated in tests on mice: when the researchers switched off SCF's function, the alpha-synuclein fibrils were no longer cleared up in the nerve cells. Instead, they accumulated in the cells and spread throughout the brain.
The more active the SCF complex, the more the alpha-synuclein fibrils are cleared, which could slow down or eventually stop the progression of such neurodegenerative diseases. The SCF complex is very short-lived, dissipating within minutes. Therapeutic approaches would focus on stabilising the complex and increasing its ability to interact with alpha-synuclein fibrils. For example, drugs could be developed for this purpose. "However, when it comes to potential therapies, we're still right at the beginning. whether effective therapies can be developed is still unclear."
Extremely Long Lived Cells are Found in Many Tissues, Not Just the Brain
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Researchers here report that the brain is not the only organ to exhibit cells that are as long-lived as the animal containing them. A number of other organs contain at least some long-lived cells, even for tissues thought to be highly regenerative and in which tissue turnover is comparatively rapid, such as the liver. It remains to be seen as to how this new information interacts with present thinking on the damage of aging, in which there is a central role for a reduction in stem cell activity and consequent loss of new cells generated to replace old tissue populations.
Scientists once thought that neurons, or possibly heart cells, were the oldest cells in the body. Now, researchers have discovered that the mouse brain, liver, and pancreas contain populations of cells and proteins with extremely long lifespans - some as old as neurons. "We were quite surprised to find cellular structures that are essentially as old as the organism they reside in. This suggests even greater cellular complexity than we previously imagined and has intriguing implications for how we think about the aging of organs, such as the brain, heart, and pancreas."
Since the researchers knew that most neurons are not replaced during the lifespan, they used them as an "age baseline" to compare other non-dividing cells. The team combined electron isotope labeling with a hybrid imaging method (MIMS-EM) to visualize and quantify cell and protein age and turnover in the brain, pancreas and liver in young and old rodent models. To validate their method, the scientists first determined the age of the neurons, and found that - as suspected - they were as old as the organism. Yet, surprisingly, the cells that line blood vessels, called endothelial cells, were also as old as neurons. This means that some non-neuronal cells do not replicate or replace themselves throughout the lifespan.
The pancreas, an organ responsible for maintaining blood sugar levels and secreting digestive enzymes, also showed cells of varying ages. A small portion of the pancreas, known as the islets of Langerhans, appeared to the researchers as a puzzle of interconnected young and old cells. Some beta cells, which release insulin, replicated throughout the lifetime and were relatively young, while some did not divide and were long-lived, similar to neurons. Yet another type of cell, called delta cells, did not divide at all. The pancreas was a striking example of age mosaicism, i.e., a population of identical cells that are distinguished by their lifespans.
Prior studies have suggested that the liver has the capacity to regenerate during adulthood, so the researchers selected this organ expecting to observe relatively young liver cells. To their surprise, the vast majority of liver cells in healthy adult mice were found to be as old as the animal, while cells that line blood vessels, and stellate-like cells, another liver cell type, were much shorter lived. Thus, unexpectedly, the liver also demonstrated age mosaicism.
Cellular Antioxidant Defenses Measured in Blood Samples Decline with Age
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Cells are in a constant state of generating oxidative molecules, clearing those molecules via the use of antioxidant proteins, and repairing the damage caused by oxidative reactions. Researchers here show that aging is accompanied by declining amounts of the natural antioxidants involved in clearing oxidizing molecules from cells, preventing them from reacting with cellular machinery to cause damage. This is an unfortunate downstream consequence of the underlying causes of aging, one that will cause further dysfunction in cells. Exactly how and why this is a feature of aging, the exact chain of cause and effect that leads from the underlying damage to this result, remains to be determined. At the present time, the fastest approach to answering that sort of inquiry is likely to build rejuvenation biotechnologies that can repair specific forms of molecular damage thought to cause aging, and then see what happens when the therapies are applied in animal studies.
An integral part of aerobic metabolism is reactive oxygen species (ROS) generation which should be analyzed according to its two main functions. On the one hand, ROS plays an important role in biomodulating and regulating many cellular functions, such as defense against pathogens, signal transduction processes during transmission of intercellular information, and activation of specific transcription factors. On the other hand, an excessive quantity of ROS has a deleterious effect on cells, reacting with a variety of molecules and thereby interfering with cellular functions. To cope with the elevated generation of ROS, ROS-scavenging biochemical pathways have been developed in aerobic cells.
In recent years there have been a lot of studies supporting the role of ROS in molecular aging mechanisms. The confirmation of oxidative stress increase with age of diverse organisms, and the generation of transgenic invertebrates overexpressing the antioxidant enzymes with increased lifespan were among the most important results of these studies. Nevertheless, there were no alterations in the lifespan in most of the examined mouse models, which under- or overexpressed a wide variety of genes coding for antioxidant enzymes. Thus, the role of oxidative stress in aging mammals is not fully understood and still demands further inquiries.
In this study, analysis of antioxidant defense was performed on the blood samples from 184 "aged" individuals aged 65-90+ years, and compared to the blood samples of 37 individuals just about at the beginning of aging, aged 55-59 years. Statistically significant decreases of Zn,Cu-superoxide dismutase (SOD-1), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were observed in elderly people in comparison with the control group. Moreover, an inverse correlation between the activities of SOD-1, CAT, and GSH-Px and the age of the examined persons was found. No age-related changes in glutathione reductase activities and malondialdehyde concentrations were observed. These lower activities of fundamental antioxidant enzymes indicate the impairment of antioxidant defense in the erythrocytes of elderly people.
Towards Bioprinted Corneas
https://www.fightagi...rinted-corneas/
While no tissues can be said to be simple, some are simpler than others. In the past decade, tissue engineers have made considerable progress towards the manufacture of these simpler tissues, from the starting point of cells and scaffold materials. Bioprinting, a form of rapid prototyping, has proven to be an important class of approach. The research noted here is a representative example of progress towards the production of corneas to replace those that are damaged by accident or age, and thus eliminate the need for donor tissue.
When a person has a severely damaged cornea, a corneal transplant is required. For this reason, many scientists have put their efforts in developing an artificial cornea. The existing artificial cornea uses recombinant collagen or is made of chemical substances such as synthetic polymer. Therefore, it does not incorporate well with the eye or is not transparent after the cornea implant. Now, researchers have 3D printed an artificial cornea using the bioink which is made of decellularized corneal stroma and stem cells. Because this cornea is made of corneal tissue-derived bioink, it is biocompatible, and 3D cell printing technology recapitulates the corneal microenvironment, therefore, its transparency is similar to the human cornea.
The human cornea is organized in a lattice pattern of collagen fibrils. The lattice pattern in the cornea is directly associated with the transparency of cornea, and many researches have tried to replicate the human cornea. However, there was a limitation in applying to corneal transplantation due to the use of cytotoxic substances in the body, their insufficient corneal features including low transparency, and so on. To solve this problem, the research team used shear stress generated in the 3D printing to manufacture the corneal lattice pattern and demonstrated that the cornea by using a corneal stroma-derived decellularized extracellular matrix bioink was biocompatible.
In the 3D printing process, when ink in the printer comes out through a nozzle and passes through the nozzle, frictional force produces shear stress. The research team successfully produced transparent artificial cornea with the lattice pattern of human cornea by regulating the shear stress to control the pattern of collagen fibrils. The research team also observed that the collagen fibrils remodeled along with the printing path create a lattice pattern similar to the structure of native human cornea after 4 weeks in vivo.
The Contribution of Reactive Astrocytes to Neurodegeneration
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Neurodegenerative diseases have a strong inflammatory component, the dysregulation of the immune system in the brain, with consequences to tissue function. In the process of astrogliosis, the supporting cells known as astrocytes react to damaging or inflammatory circumstances, and radically change their behavior. This can help in the short term for some forms of injury to the central nervous system, but is harmful when it continues for the long term. Like microglia, another supporting cell type, astrocytes can adopt different packages of behaviors, or phenotypes, and switch back and forth between them in response to circumstances. The primary distinction of interest in these is between (a) a supportive, regenerative phenotype, and (b) an aggressive, inflammatory phenotype. The latter tends to show up ever more often as aging progresses, and this imbalance is the cause of further harms.
Astrocytes are the most abundant cells with various structures and functions and are ubiquitous in all regions of the central nervous system (CNS). Astrocytes are associated with various aspects of physiological functions, including secretion of nutrients, maintenance of neuronal microenvironment, regulation of the permeability of the blood-brain barrier and the development of pathological processes in the brain. Studies on mouse models have shown that astrocytes play a complex role in the pathogenesis of neurodegenerative diseases, and the dysfunction of astrocytes may contribute to either neuronal death or the process of neural disturbances. It has been found that reactive astrocytes always lose their supportive role and gain toxic function in the progression of neurodegenerative diseases.
During brain insult or neurodegeneration process, astrocytes can respond to pathological changes by releasing extracellular molecules, such as neurotrophic factors (for example BDNF, VEGF, and bFGF), inflammatory factors (including IL-1β, TNF-α, and NO, etc.) and cytotoxins (such as Lcn2) through reactive astrogliosis. As a result, they play either a neuroprotective or neurotoxic role (such as provoking inflammation or increasing damages) in the CNS. It has been shown that the specific deletion of STAT3 in astrocytes can cause reactive gliosis, which leads to increased level of inflammation, tissue damage as well as compromised motor recovery after spinal cord injury. Interestingly, some studies have shown that the activation of NF-κB in astrocytes contributes to the pathogenesis of CNS, and inhibition of this signaling pathway can limit tissue damage.
These findings suggest that astrocytes may play a protective role through STAT3 signaling pathways in some neurodegenerative lesions, while NF-κB signals may mediate neurotoxicity. In analogy to the "M1" and "M2" phenotype categories for macrophages, recent studies have reported that neural inflammation and ischemia can induce two types of reactive astrocytes, termed "A1" and "A2", respectively. Gene transcriptome analysis of reactive astrocytes shows that A1 reactive astrocytes (A1s) can upregulate many classical complement cascade genes that are destructive to synapses, and secret neurotoxins that have not yet been well identified. In contrast, A2 reactive astrocytes (A2s) can upregulate many neurotrophic factors, which can promote either the survival and growth of neurons or the synaptic repair. Thus, A1s may have "harmful" features, while A2s may carry "useful" or repair functions. So far, it remains unclear what the possible signaling pathways have been involved in inducing the phenotypes of A1s and A2s in the process of different initiating CNS injuries.
People Remain Hopeful that Something Useful can be Accomplished with Minoxidil
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Minoxidil is, of course, the well known basis for certain popular hair growth products. That outcome was an accident, however, as the compound originally entered clinical trials - some 30 years ago - as a possible treatment for hypertension, or chronic raised blood pressure. The primary mechanism of interest is that minoxidil spurs greater deposition of elastin in blood vessel walls and other tissues, thereby reversing a fraction of the progressive loss of elastin that takes place over the course of aging.
Elastin, as one might guess from the name, is a component of the extracellular matrix responsible for the elasticity exhibited by tissues such as skin and blood vessels. Hypertension is caused by the age-related stiffening of blood vessels, which leads to a dysregulation of pressure control systems in our biochemistry. This then speeds up the progression of atherosclerosis and heart failure, and in addition produces an accelerated rate of capillary rupture and consequent damage in delicate tissues such as the brain and kidney. It is a very import aspect of age-related degeneration.
It is interesting to see researchers still working on minoxidil. The original clinical trials for hypertension, while leading to an approved drug, showed that minoxidil causes edema around the heart at useful doses for the elastin deposition effect, a potentially severe consequence. For me, that is more than enough to reconsider its use in this way. During the early studies and trials, hair growth in the patients was noted, and the rest of the development program thereafter is history. It is possible that now, with a far greater ability to take a small molecule as a starting point and build different versions with different characteristics, it is plausible to build a minoxidil analog that doesn't have the serious side-effects at usefully high doses, where that was simply not possible in earlier decades. We shall see.
Arterial wall elastic fibers, made of 90% elastin, are arranged into elastic lamellae which are responsible for the resilience and elastic properties of the large arteries (aorta and its proximal branches). Elastin is synthesized only in early life and adolescence mainly by the vascular smooth muscle cells (VSMC) through the cross-linking of its soluble precursor, tropoelastin. In normal aging, the elastic fibers become fragmented and the mechanical load is transferred to collagen fibers, which are 100-1000 times stiffer than elastic fibers.
Minoxidil, an ATP-dependent K+ channel opener, has been shown to stimulate elastin expression in vitro and in vivo in the aorta of young adult hypertensive rats. Here, we have studied the effect of a 3-month chronic oral treatment with minoxidil (120 mg/L in drinking water) on the abdominal aorta structure and function in adult (6-month-old) and aged (24-month-old) male and female mice. Our results show that minoxidil treatment preserves elastic lamellae integrity, which is accompanied by the formation of newly synthesized elastic fibers in aged mice. This led to a generally decreased pulse pressure and a significant improvement of the arterial biomechanical properties in female mice, which present an increased distensibility and a decreased rigidity of the aorta. Our studies show that minoxidil treatment reversed some of the major adverse effects of arterial aging in mice and could be an interesting anti-arterial aging agent, also potentially usable for young female-targeted therapies.
Talking with Laura Deming: Aging is the World's Most Important Problem
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Laura Deming is one of the people influential in the sweeping shift of the past few years in research and development of therapies to treat aging, in which rejuvenation biotechnologies such as senolytic therapies finally started the move from the laboratory into startup companies, on the way to the clinic. She founded the first venture fund to specialize in what people are now calling the longevity sector of the biotech industry, somewhat before that longevity sector actually existed in any meaningful way. Now, of course, funding is pouring into this area of development; the years ahead will be interesting. Now is very much the time for entrepreneurs to step up, find viable projects in aging and longevity, raise the funds, and carry them forward into clinical development.
At 25, Laura Deming has already achieved more in her chosen field - anti-ageing - than many people twice her age. At 12 she was researching the biology of ageing in the laboratory of one of the world's leading scientists; at 14 she went to study physics at MIT, only to drop out at 17 and start a venture capital fund under the guidance of Silicon Valley entrepreneur Peter Thiel. Aubrey de Grey, the English gerontologist who has suggested that humans might live to be 1,000, calls Deming an "utter genius" for her scientific and investment "brilliance".
There is a long history of charlatans selling the cure to getting old. However, Deming is no biohacker; she isn't fiddling with diet, exercise, or pills to add an extra year or two to her life. Her ambition is far greater: to accelerate anti-ageing science so that everyone can live healthier lives for longer. To that end, she founded the Longevity Fund in 2011, when she was still a teenager, to invest in biotech companies making treatments for age-related diseases.
When Deming decided to start raising money to get anti-ageing research out of the lab, she was still too young to sign the paperwork - her father had to do it on her behalf. She received some advice from Peter Thiel but confesses that she really did not know what she was doing. "You'd google 'How to start a venture capital fund' and there were just no articles," she says, amazed. For the first two years of the fund, Deming tried to sell investors on the "science and the humanitarian issues at stake". "Honestly, for two years I gave the same pitch of, here's a 20 billion market and here's all the people who are dying, can someone help them? And everyone was like, 'That's amazing, you're such a good person', and nobody invested," she laughs. She learned she needed to link her passion for the cause to a "very concrete business case".
The fund's first investment, in Unity Biotechnology, helped her to do that. Unity is developing a drug that targets senescent cells - decrepit cells that refuse to die. If it works, the drug could be used to treat age-related diseases such as osteoarthritis, eye diseases, and pulmonary diseases. Unity went public last year and now has a valuation of more than 350 million. "Having a concrete case to show potential investors ... that was what brought it together." Deming's biggest fear is the hype cycle: what if a few early anti-ageing trials flop, and the money goes away? "That gives me a lot of fear, because it's a field that is still very early. There's a lot of stuff that's still being figured out, and I think a lot of things will fail."
View the full article at FightAging
