Fight Aging! Newsletter, September 26th 2022

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  • Nintedanib as a Potential Senolytic Drug
  • Towards Reprogramming with Small Molecules
  • Understanding a Natural Mechanism of Lysosomal Repair
  • Antigen Presenting Cells Donate Telomeres to T Cells to Increase their Longevity
  • Continued Hope that Amyloid-β is the Cause of Alzheimer's Disease, an Amyloid Cascade Hypothesis 2.0
  • β2-microglobulin in Buccal Cells as a Biomarker of Aging
  • Rapamycin, Acarbose, and Phenylbutyrate Combination Slows Cognitive Decline in Mice
  • Irisin Mediates the Effects of Physical Exercise on Parkinson's Disease Progression
  • Vitronectin May Contribute to Calcification in Tissues
  • Accelerometer Measures of Activity and Dementia Risk
  • Decreased SPARC in Fat Tissue Reduces Chronic Inflammation
  • Immunotherapy Destroys Activated Fibroblasts to Reduce Fibrosis
  • Age-Related Inflammation Makes ɑ-synuclein Aggregation Worse
  • Summarizing the State of Aging Research
  • Targeting Fibroblasts to Enable Scarless Healing

Nintedanib as a Potential Senolytic Drug

Senescent cells accumulate with age, and their presence contributes to chronic inflammation and many other age-related disruptions to normal tissue function. Academia and industry are engaged in many programs aimed at the creation of senolytic treatments that can selectively destroy senescent cells. The most proven senolytic treatment to date is the dasatinib and quercetin combination, shown to partially clear senescent cells from tissues in both old mice and old humans. Dasatinib is a tyrosine kinase inhibitor, and here researchers report their evidence in support another tyrosine kinase inhibitor, nintedanib, to be usefully senolytic.

Will nintedanib prove to be better or worse than dasatinib? That is hard to say, and different members of the same class of drugs can vary widely in all characteristics. The evidence here should be balanced against the history of nintedanib, given that it is approved for use in slowing the progression of idiopathic pulmonary fibrosis, and has been used for some years in that role. Senescent cells are thought to contribute to the development of idiopathic pulmonary fibrosis, and the dasatinib and quercetin combination showed promise in a small clinical trial for idiopathic pulmonary fibrosis patients. Animal data suggests dasatinib to be much less senolytic on its own, without quercetin, but no-one has yet earnestly tried to combine nintedanib and quercetin. Time will tell as to which senolytic approaches are the most useful.

Nintedanib induces senolytic effect via STAT3 inhibition

Selective removal of senescent cells, or senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even for reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced the death of primary human dermal fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without inducing cytotoxicity.

Interestingly, the mechanism by which nintedanib activated caspase-9 in the intrinsic apoptotic pathway differed from that of ABT263 apoptosis induction; specifically, nintedanib did not decrease the levels of Bcl-2 family proteins in senescent cells. Moreover, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused the drug-induced death of senescent cells. STAT3 knockdown in senescent cells induced caspase activation. Moreover, nintedanib reduced the number of senescence-associated β-galactosidase-positive senescent cells in parallel with a reduction in STAT3 phosphorylation and ameliorated collagen deposition in a mouse model of bleomycin-induced lung fibrosis. Consistently, nintedanib exhibited a senolytic effect through bleomycin-induced senescence of human pulmonary fibroblasts.

Overall, we found that nintedanib can be used as a new senolytic agent and that inhibiting STAT3 may be an approach for inducing the selective death of senescent cells. Our findings pave the way for expanding the senolytic toolkit for use in various aging statuses and age-related diseases.

Towards Reprogramming with Small Molecules

A great deal of modern medicine starts out as genetic studies in cells and animal models, but then the programs abandon genetics to use small molecules to produce a small fraction of the effect of the genetic alteration of interest. The reasons for this have a lot to do with the high cost of regulation and conservatism of funding sources, to the point at which the development of a poor therapy using well-proven approaches is very much favored over the development of a much better therapy using new approaches. In the broader sense, in the longer term, the true promise of gene therapies, the various approaches that dial up and dial down the expression of specific genes, is that the research and development industry can stop producing treatments that are objectively bad in comparison to the alterations of gene expression that inspired them.

Given the state of the industry today, however, one should absolutely expect that any promising form of therapy derived from genetic studies will be the subject of intense effort to translate it into a small molecule treatment that produces only a fraction of the benefits. So it goes with cellular reprogramming as an approach to rejuvenation, resetting epigenetic patterns in old cells by overexpressing the Yamanaka factors, typically for only a short period of time. Researchers are trying to find combinations of small molecules that tinker with transcription factor expression or downstream mechanisms to use in place of the mRNA therapies currently employed for partial reprogramming of cells in animal studies. It will be interesting to see the degree to which they succeed as this initiative moves forward in the years ahead.

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan

The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown.

Here, we demonstrated that partial chemical reprogramming is able to improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan by 42%. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical induced partial reprogramming, opening a path towards future translational applications.

Understanding a Natural Mechanism of Lysosomal Repair

Lysosomes are membrane-bound packages of enzymes found in cells. They recycle damaged and excess molecules and structures in the cell by breaking them down into raw materials that can be reused for protein synthesis. This activity is vital to cell health, and dysfunction of lysosomes is a noted feature of aging. Thus it is interesting to see a greater understanding of the ways in which cells maintain lysosomes, as outlined in today's research materials. The focus is on the repair of lysosomal membranes, a process that may break down with age, and thus some degree of benefit might be achieved by enhancing this repair. The first step on that road is to understand which proteins are involved, and thus might be targets for manipulation.

That said, it is isn't at all clear that this issue of membrane damage is the important aspect of lysosomal decline in later life. Another issue involves the accumulation of cellular waste materials that the lysosome cannot break down, which occurs in inherited lysosomal storage conditions due to loss of function mutation that robs an individual of one or more essential lysosomal enzymes, but also over the course of aging in long-lived cells. In old individuals, this mix of problem waste molecules is called lipofuscin, and lysosomes become bloated with it, unable to perform their usual tasks. Cells fall into a garbage catastrophe and become dysfunctional or die. Membrane repair is most likely not all that relevant to lysosomal performance in this situation.

Scientists Discover How Cells Repair Longevity-Promoting 'Recycling System'

As the cell's recycling system, lysosomes contain potent digestive enzymes that degrade molecular waste. These contents are walled off from damaging other parts of the cell with a membrane that acts like a chain link fence around a hazardous waste facility. Although breaks can occur in this fence, a healthy cell quickly repairs the damage. An enzyme called PI4K2A accumulated on damaged lysosomes within minutes and generated high levels of a signaling molecule called PtdIns4P, which recruits other molecules called ORPs. ORP proteins work like tethers. One end of the protein binds to the PtdIns4P red flag on the lysosome, and the other end binds to the endoplasmic reticulum, the cellular structure involved in synthesis of proteins and lipids.

The endoplasmic reticulum wraps around the lysosome like a blanket. Normally, the endoplasmic reticulum and lysosomes barely touch each other, but once the lysosome was damaged, researchers found that they were embracing. Through this embrace, cholesterol and a lipid called phosphatidylserine are shuttled to the lysosome and help patch up holes in the membrane fence. Phosphatidylserine also activates a protein called ATG2, which acts like a bridge to transfer other lipids to the lysosome, the final membrane repair step in the newly described PITT - or phosphoinositide-initiated membrane tethering and lipid transport - pathway.

The researchers suspect that in healthy people, small breaks in the lysosome membrane are quickly repaired through the PITT pathway. But if the damage is too extensive or the repair pathway is compromised - due to age or disease - leaky lysosomes accumulate. In Alzheimer's, leakage of tau fibrils from damaged lysosomes is a key step in progression of the disease.

A phosphoinositide signalling pathway mediates rapid lysosomal repair

Lysosomal dysfunction has been increasingly linked to disease and normal ageing. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair.

Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11, and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair.

Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.

Antigen Presenting Cells Donate Telomeres to T Cells to Increase their Longevity

T cells replicate aggressively in response to infection and other threats, yet these cells must also persist in the body for years in order to maintain immunological memory. Telomeres, repeated DNA sequences at the ends of chromosomes, shorten with each cell division. This mechanism forms a part of the Hayflick limit on somatic cell replication. When telomeres become too short, cells become senescent and self-destruct, or are destroyed by immune cells. T cells can employ telomerase to lengthen telomeres, but not to any great degree. So how do they manage such long lives in an environment of repeated threats by pathogens, and thus repeated bursts of telomere-shortening replication?

In today's open access paper, the authors outline a fascinating mechanism by which antigen-presenting B cells, which interact with T cells to coordinate the immune response, donate telomeres to those T cells, thereby increasing their replicative life span. One initial thought in response to this finding is that it should be possible to create telomere-bearing vesicles to replicate this effect, more broadly than it occurs naturally. As is the case for telomerase gene therapy, and all such analogous approaches aimed at lengthening telomeres, there is the issue of selectivity, however. Extending telomeres in cells that probably should be destroyed as well as those that will continue beneficial work is a concern, even given the very positive data in mice resulting from upregulation of telomerase.

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory

The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse.

Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.

How senescent T cells are formed remains poorly understood. We propose a model whereby telomere transfer from APCs protects the recipient T cells from replicative senescence. The recipient is preferably a naïve or central memory T cell. When recipient T cells acquire telomeres from APCs during antigen presentation, they shift towards a stem-like/central long-lived memory state. Failure to acquire telomeres skews them towards senescence instead.

It is not clear how T cells with APC telomeres will divide upon telomere transfer; however, these T cells may subsequently divide and differentiate both linearly and/or asymmetrically after antigen stimulation, if telomere transfer occurs. It is possible that antigen strength may affect the amount of telomere transfer and subsequent division of T cells. However, even in situations where antigen specificity was identical, a large proportion of T cells still failed to acquire telomeres from APCs, shifting towards a short-lived effector state; some of these cells may serve as senescent progenitors. Therefore, additional mechanisms that control telomere transfer during the process of antigen, presentation beyond T-cell receptor specificity, would have to exist.

We suggest that senescent T cells, or their progenitors, may be short-lived cells that are continuously generated by episodes of activation that lack telomere transfer. An important but as-yet-undefined function of the immunological synapse is, therefore, immediate determination of senescence fates of T cells. The intercellular telomere transfer reaction we described is a different form of decentralized immunity whereby APCs distribute telomeres to favour some T cells becoming long-lived memory cells, bypassing senescence. Decentralization indicates that T cells do not rely on just a single molecule, telomerase, to extend telomeres. Whether the memory T cells generated in the absence of telomere transfer have the same longevity outlook than those telomere-acquiring T cells we have studied remains to be determined.

Continued Hope that Amyloid-β is the Cause of Alzheimer's Disease, an Amyloid Cascade Hypothesis 2.0

Is the slow amyloid-β aggregation, occurring for years prior to the onset of evident symptoms, really the cause of Alzheimer's disease? The amyloid cascade hypothesis suggests that this accumulation of misfolded amyloid-β, and the toxic biochemistry surrounding its aggregates, set the stage for the much more severe later stage of Alzheimer's disease, in which neuroinflammation and tau aggregation kill neurons - and ultimately the patient. The hypothesis makes sense given what is known of the relevant biochemistry, but has been strongly challenged by (a) the great difficulty in clearing amyloid-β from the brain, a project that took decades to produce successful therapies, and (b) that successful clearance has failed to produce meaningful patient benefits.

The biochemistry of the brain is exceptionally complex, and the failure of amyloid-β clearance to help patients may not in fact imply that the amyloid cascade hypothesis is very wrong. "Very wrong" in this context could mean that, for example, the aggregation of amyloid-β is a side-effect, a consequence of other processes that actually drive the onset of Alzheimer's, and thus targeting it will never prove to be useful. Or it could mean that while amyloid-β is a meaningful component of the condition, it is not sufficient to clear it without also repairing the vasculature, or removing senescent cells, or damping down neuroinflammation. However, it may also be the case that amyloid-β is in fact a useful target, and the failure to help patients occurred because the wrong forms or localizations of amyloid-β were targeted, or that patients were treated too late in the progression of Alzheimer's disease, after a point at which amyloid-β became irrelevant.

Biochemistry is complicated! Researchers have devoted a great deal of thought in recent years to amending the amyloid cascade hypothesis in ways that could explain the failure of successful clearance to help patients. Today's open access paper is one example of a modified amyloid cascade hypothesis, an attempt to reconcile what is known into a unified understanding. It may well be just as wrong as other views of Alzheimer's disease.

The Amyloid Cascade Hypothesis 2.0: On the Possibility of Once-in-a-Lifetime-Only Treatment for Prevention of Alzheimer's Disease and for Its Potential Cure at Symptomatic Stages

We posit that Alzheimer's disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway, which is activated by AβPP-derived Aβ accumulated intraneuronally, in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal-Aβ (iAβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived iAβ triggers relatively benign cascade that activates the AβPP-independent iAβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss.

The entire output of the AβPP-independent iAβ-generating pathway is retained intraneuronally and perpetuates the pathway's operation. This process constitutes a self-propagating, autonomous engine that drives AD and ultimately kills its host cells. Once activated, the AD Engine is self-reliant and independent from Aβ production in the AβPP proteolytic pathway; operation of the former renders the latter irrelevant to the progression of AD by relegating its iAβ contribution to insignificance, and making its manipulation for therapeutic purposes, such as via BACE (beta-site AβPP-cleaving enzyme) inhibition, as futile.

In the proposed AD paradigm, the only valid direct therapeutic strategy is targeting the engine's components, and the most effective feasible approach appears to be the activation of BACE1 and/or of its homolog BACE2, with the aim of exploiting their Aβ-cleaving activities. Such treatment would collapse the iAβ population and 'reset' its levels below those required for the operation of the AD Engine. Any sufficiently selective iAβ-depleting treatment would be equally effective. Remarkably, this approach opens the possibility of a short-duration, once-in-a-lifetime-only or very infrequent, preventive or curative therapy for AD; this therapy would be also effective for prevention and treatment of the 'common' pervasive aging-associated cognitive decline.

The ACH2.0 clarifies all ACH-unresolved inconsistencies, explains the widespread 'resilience to AD' phenomenon, predicts occurrences of a category of AD-afflicted individuals without excessive Aβ plaque load and of a novel type of familial insusceptibility to AD; it also predicts the lifespan-dependent inevitability of AD in humans if untreated preventively. The article details strategy and methodology to generate an adequate AD model and validate the hypothesis; the proposed AD model may also serve as a research and drug development platform.

β2-microglobulin in Buccal Cells as a Biomarker of Aging

Researchers here note that expression of β2-microglobulin rises with age in cells of the inner cheek, correlating with p16 expression, a marker of cellular senescence. β2-microglobulin is connected to inflammation, and senescent cell burden is one of the more important contributions to the chronic inflammation of old age. One can never have too many biomarkers of age, even if they are individually only loosely correlated with age, as combining them can in principle produce better and more accurately correlated metrics.

β2-microglobulin (β2M) is a small protein that is expressed in all nucleated cells, previous data showed that its activity increases during inflammation. β2M interplays with cytokines for instance, IL-6, IL-8 and others intracellularly to induce inflammatory responses. In addition, it can bind and modulate the activity of growth factors and hormones and receptors. β2M has been exploited as a biomarker for many disorders with inflammatory components.

Our group previously showed that β2M expressed highly in senescent cells, and recently it has been shown by our group that β2M expressed highly in blood samples of old people comparing to youngers. Furthermore, we have shown that β2M correlated significantly with oxidative stress biomarkers, which could underscore a potential role in oxidative stress network. Therefore, there is a rationality to test the expression of β2M across different group of age using other easier source of sample such as buccal cells.

Buccal cells are epithelial cells that are similar to brain and skin in nature. Buccal cells can be collected easily, deriving a high number of cells that can be used for different biological assays. Comparing to other sample methods, buccal cell samples are less invasive and very easy to collect. In addition, buccal cells are very stable after isolation from the mouth, which makes them easy to process and analyze. Moreover, buccal cells are easy to preserve, making them an easy source for diagnosis.

In this study, we used buccal cells to examine the expression of β2M in different age groups. The expression of β2M increased significantly with fold change 3.40, 4.80, 6.60, 8.20 and 12.04 for the group of age 18-25 years, 26-35 years, 36-45 years, 46-55 years, and 56-70 years respectively. The same observation was seen with markers of biological aging (p16INK4a) with fold change 3.19, 3.90, 4.80, 8.50 and 12.40 for the group of age 18-25 years, 26-35 years, 36-45 years, 46-55 years, and 56-70 years respectively.

As expected, there was an increase in expression of inflammatory genes (IL-1β and IL-6) in the elderly. Moreover, there was a direct significant correlation (Pearson correlation coefficient, r = 90) between β2M expression and age, and the same direct significant correlation between p16INK4a expression and age was also seen (r = 90). In addition, a direct correlation between β2M and p16INK4a was also seen (r = 0.83), there was also direct correlation between β2M and IL-1β (r = 0.5) and IL-6 (r = 0.68).

This evidence showed that β2M increased in buccal cells of the elderly compared to younger, and thereby buccal cells can be exploited to assess biological aging by measuring β2M levels, however, large sample size and using another assessing method such as β2M protein levels should be performed to confirm the results.

Rapamycin, Acarbose, and Phenylbutyrate Combination Slows Cognitive Decline in Mice

You might recall that researchers recently reported that the combination of rapamycin, acarbose, and phenylbutyrate appear to meaningfully improve physical function in old mice. Here, the same team reports on the efforts of this intervention on cognitive function in mice. Individually, these treatments, applied over the long term, are all shown to slow aging to some degree in mice. It remains to be seen whether combination treatments of this sort, upregulation of cellular stress responses, mimicking aspects of the cellular response to exercise and calorie restriction, will be as useful in humans. It is the case that life span is not greatly affected by this type of strategy in long-lived mammals, only in short-lived mammals do adjustments to metabolism mimicking calorie restriction produce sizable life extension.

Aging is a primary risk factor for cognitive dysfunction and exacerbates multiple biological processes in the brain, including but not limited to nutrient sensing dysregulation, insulin sensing dysfunction and histone deacetylation. Therefore, pharmaceutical intervention of aging targeting several distinct but overlapping pathways provides a basis for testing combinations of drugs as a cocktail. A recent study showed that middle-aged mice treated with a drug cocktail of rapamycin, acarbose, and phenylbutyrate for three months had increased resilience to age related cognitive decline. This finding provided the rationale to investigate the comprehensive transcriptomic and molecular changes within the brain of mice that received this cocktail treatment or control substance.

Transcriptome profiles were generated through RNA sequencing and pathway analysis was performed by gene set enrichment analysis to evaluate the overall RNA message effect of the drug cocktail. Molecular endpoints representing aging pathways were measured through immunohistochemistry to further validate the attenuation of brain aging in the hippocampus of mice that received the cocktail treatment, each individual drug or controls. Results indicated that biological processes that enhance aging were suppressed, while autophagy was increased in the brains of mice given the drug cocktail. The molecular endpoint assessments indicated that treatment with the drug cocktail was overall more effective than any of the individual drugs for relieving cognitive impairment by targeting multiple aging pathways.

Irisin Mediates the Effects of Physical Exercise on Parkinson's Disease Progression

Exercise is known to slow the progression of Parkinson's disease, or at least attenuate the symptoms. What is the underlying mechanism? Researchers here suggest that the myokine signal protein irisin accounts for much of this, by promoting greater removal of problematic α-synuclein aggregates. Parkinson's disease is associated with α-synuclein misfolding and consequent aggregation, these toxic versions of a normally helpful protein spreading through the central nervous system over time to cause cell death and dysfunction in vulnerable populations of neurons. Clearing misfolded α-synuclein seems a viable strategy, given the right approach, something much more potent than the effects of exercise.

Physical exercise is thought to have beneficial effects on the symptoms of Parkinson's disease (PD). Irisin is an exercise-induced myokine released into the circulation. We therefore tested whether irisin itself could have a beneficial effect on pathologic α-synuclein (α-syn) accumulation and concomitant neurodegeneration in PD.

Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test.

In vitro, recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.

Vitronectin May Contribute to Calcification in Tissues

The interesting research noted here implicates pressure-based changes in the structure of vitronectin as a mediating mechanism linking raised blood pressure and ocular pressure and calcification in tissues. Calcification results from changes in cell behavior that lead to calcium deposition akin to that occurring in bone tissue, but in inappropriate locations such as blood vessel walls. This is disruptive of structure and function, a facet of aging that should be addressed as a part of any comprehensive package of rejuvenation therapies.

"Proteins in the blood are under constant and changing pressure because of the different ways blood flows throughout the body. For example, blood flows more slowly through small blood vessels in the eyes compared to larger arteries around the heart. Blood proteins need to be able to respond to these changes, and this study gives us fundamental truths about how they adapt to their environment, which is critical to targeting those proteins for future treatments."

There are hundreds of proteins in our blood, but the researchers focused on vitronectin, one of the most abundant. In addition to circulating in high concentrations in the blood, vitronectin is found in the scaffolding between cells and is also an important component of cholesterol. "This protein is an important target for macular degeneration because it accumulates in the back of the eye, causing vision loss. Similar deposits appear in the brain in Alzheimer's disease and in the arteries in atherosclerosis. We want to understand why this happens and leverage this knowledge to develop new treatments."

To approach this question, the researchers were interested in learning how the protein changes its structure at different temperatures and under different levels of pressure, approximating what happens in the human body. Through detailed biochemical analysis, the researchers found that the protein can subtly change its shape under pressure. These changes cause it to bond more easily to calcium ions in the blood, which the researchers suggest leads to the buildup of calcified plaque deposits characteristic of macular degeneration and other age-related diseases. "It's a very subtle rearrangement of the molecular structure, but it has a big impact on how the protein functions. The more we learn about the protein on a structural and mechanistic level, the better chance we have of successfully targeting it with treatments."

Accelerometer Measures of Activity and Dementia Risk

Unsurprisingly, given other data on exercise and aging, researchers here show that greater activity correlates with a reduced risk of suffering dementia. The data in this study comes from accelerometer devices, counting steps and intensity. The introduction of accelerometers over the past few decades has led to a considerable improvement in the quality of epidemiological data relating to physical activity, particularly the relationship between low levels of activity and health. Any increment above being sedentary provides a meaningful improvement, relative to the harms done by inactivity, but the optimal level of activity is somewhat higher than that.

Step-based recommendations may be appropriate for dementia-prevention guidelines. However, the association of step count and intensity with dementia incidence is unknown. This study examined the dose-response association between daily step count and intensity and incidence of all-cause dementia among adults in the UK. This was a UK Biobank prospective population-based cohort study (February 2013 to December 2015) with 6.9 years of follow-up (data analysis conducted May 2022). A total of 78,430 of 103,684 eligible adults aged 40 to 79 years with valid wrist accelerometer data were included. Registry-based dementia was ascertained through October 2021.

We found no minimal threshold for the beneficial association of step counts with incident dementia. Our findings suggest that approximately 9,800 steps per day may be optimal to lower the risk of dementia. We estimated the minimum dose at approximately 3,800 steps per day, which was associated with 25% lower incident dementia. This finding suggests that population-wide dementia prevention might be improved by shifting away from the least-active end of the step-count distributions. Unlike previous studies investigating mortality outcomes, our analyses highlight the importance of stepping intensity for preventing dementia. Both purposeful steps and peak 30-minute cadence (i.e. an indicator of overall best natural effort in a free-living environment) were associated with lower risks of dementia.

Decreased SPARC in Fat Tissue Reduces Chronic Inflammation

SPARC is one of a number of proteins that mediate interactions between cells and the extracellular matrix. Researchers here note that SPARC is connected to the chronic inflammation of aging, and the relationship between visceral fat tissue and inflammatory signaling, perhaps largely via its influence on whether macrophages adopt inflammatory behaviors in response to their environment. Reducing the amount of SPARC in fat tissue reduces chronic inflammation and thereby improves health, and this may be a meaningful mechanism in the way in which calorie restriction produces lowered inflammation and improved health. Therapies that target SPARC might prove to be useful; any approach that lowers inappropriate inflammatory signaling in later life without impacting necessary inflammatory signaling may be promising.

The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7.

Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.

Immunotherapy Destroys Activated Fibroblasts to Reduce Fibrosis

Researchers here report on an approach to treating fibrosis via vaccination to target distinctive molecular features of activated fibroblasts, the cells that generate the scar-like deposits of excess collagen that are characteristic of fibrosis. This scarring disrupts tissue structure and function. At the present time, there are no truly effective treatments for fibrosis in the clinic, and it is a problem characteristic of old age that affects numerous vital organs, such as heart, lungs, liver, and kidneys. Approaches that can efficiently reverse the progression of fibrosis are very much needed.

Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis.

In silico epitope prediction revealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting "self-peptides" can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis.

Age-Related Inflammation Makes ɑ-synuclein Aggregation Worse

Chronic inflammation in brain tissue is a feature of neurodegenerative conditions, including those characterized by aggregation of misfolded proteins. This includes the synucleopathies, such as Parkinson's disease, in which which α-synuclein misfolds to produce toxicity, spreading through the brain to cause dysfunction and cell death. As researchers note here, this is accelerated by the presence of inflammatory signaling.

Age is the main risk factor for neurodegenerative disorders with dementia and movement dysfunction including Alzheimer's Disease (AD), Dementia with Lewy bodies (DLB), and Parkinson's Disease (PD). While in AD, amyloid beta (Aβ) and tau play a central role, in DLB and PD, ɑ-synuclein (ɑ-syn) is a key mediator. However, ɑ-syn has been shown to accumulate in the brain during aging and in AD and in DLB, Aβ, and tau are also found in conjunction with ɑ-syn in selected brain regions.

Under physiological conditions ɑ-syn is an intracellular protein that might play a role in neuroplasticity, however during aging and under pathological conditions ɑ-syn aggregates can be released to the extracellular space leading to cell to cell propagation spreading and seeding of small aggregates into preformed protofibrils (pff) and fibrils in neighboring neuronal and non-neuronal cells. Recent evidence has shown that the intrinsic structure of ɑ-syn fibrils dictates the characteristic of the synucleinopathies and for instance inoculation of selected ɑ-syn pff into the CNS can reproduce several aspects of the pathology of DLB/PD in wild type animals models.

Although protein aggregation and spreading have been extensively studied, less is known about the contribution of aging. One possibility by which aging might lead to neurodegeneration is dysregulation in immune cell function. This might be in part mediated by extracellular ɑ-syn propagating to glial cells. For example, it has been shown that ɑ-syn can activate innate immune responses via Toll like receptors.

In this study we evaluated the role of aging in neurodegeneration in the ɑ-syn pff model. We found that inoculation of ɑ-syn pff in aged mice resulted in greater spreading and deficits compared to young mice, with ɑ-syn pff-inducing gene networks in young mice that overlapped with genes differentially expressed in aged mice. We propose that changes in inflammatory gene expression underly the increased susceptibility of aged mice to enhanced ɑ-syn induced pathology and might represent a new avenue for therapeutics.

Summarizing the State of Aging Research

Providing a summary of the present state of aging research is a tall order, given the rapid growth in the field, and great breadth of work in both academia and industry, but the authors of this lengthy review paper take a swing at it. They look at areas of interest, new and well-established, apply a loose taxonomy to diverse initiatives, and attempt to draw it all together into a cohesive whole. The thrust of the field nowadays is towards intervention, attempting to slow or reverse aging in order to treat and prevent age-related disease. The important debates are over which strategies are more likely versus less likely to succeed in this goal, and thus over whether important areas of fundamental and preclinical research are underfunded or overfunded, and whether large-scale funding for clinical development is misplaced.

Aging has attracted curiosity and elicited imagination throughout human history. However, it has been only 30 years since a new epoch in aging research was established after the isolation of the first long-lived strains in C. elegans. Nowadays, studies in the aging field are exploding with the ever-expanding knowledge of the molecular and cellular bases of life and diseases, whilst subjected to scientific scrutiny. In this current review, we summarize the cutting-edge developments in aging research, presenting the landscape of aging across multiple layers.

In the first chapter, at the cellular level, we focus on cellular senescence, a main culprit of aging, harnessing a panel of phenotypes from various aspects to reveal underlying molecular alterations and mechanisms. In addition, cellular senescence bridges aging and cancer, for which aging is a major risk factor but the causal relationship still remains elusive. On one hand, cellular senescence constitutes a potent, cell autonomous anti-cancer mechanism in vivo of higher eukaryotes; on the other hand, cellular senescence accumulating with age may evoke intrinsic reprogramming of stem cells and contribute to tumor-promoting microenvironment through SASP and inflammaging.

Amongst all cell types, stem cell aging is of particular interest, as their exhaustion and dysfunction impair tissue function and regeneration capacity and lead to age-associated disorders, driving impacts way up to organismal aging. Indeed, aging is manifested as a multisystemic deterioration throughout the body that leads to declining tissue and organ functions. What we have learned about cellular aging from the first chapter are also reflected at the tissue level; and moreover, in this aging community of cells, they are affected by each other in the same tissue through the microenvironment, or even across tissues by systemic factors.

In the second chapter, we summarize aging-associated changes that occur in various tissues and organs, including those in the circulatory system, hematopoietic and immune system, nervous system, musculoskeletal system, reproductive system, digestive system as well as the microbiota therein. Collectively, understanding mechanisms and identifying targets of tissue/organ aging open vistas to therapeutic interventions for alleviating aging and age-associated disorders.

Finally, in the third chapter, we review geroprotective approaches in the hope to rewind the biological clock to a youthful state. This can be achieved by targeting key pro-/reverse-aging factors to rejuvenate aged cells, by eliminating senescent cells, or by transplanting genetically-modified stem cells. The rejuvenating effect can be local or systematic. Sophisticated strategies have been developed to deliver it through gene therapy, antibodies, or small molecule-based drugs.

We are now entering an inspiring era of aging research. According to new scientific findings summarized here and in other equivalent publications, this era now offers unprecedented hope for extending human healthspan: preventing, delaying or, even in certain cases, reversing many of the signs of aging. Whether this era promises to extend the longest human lifespan still remains an open question. However, what is clear is that after 30 years of fundamental research linking specific genes to aging, although many aspects still await further investigation, such as the interplay between metabolism and systemic aging, a solid foundation has been established, and clinical trials for interventions that target the aging process are being initiated. Although we may encounter considerable difficulties in applying this research to humans, the potential rewards in healthy aging far outweigh the risks.

Targeting Fibroblasts to Enable Scarless Healing

Regeneration without scarring is a desirable goal. Given that this ability exists in very early life in mammals, is retained in limited ways into adulthood in some mammalian species, and is exhibited in a range of other higher animals such as salamanders, it seems plausible that enabling regeneration without scarring is just a matter of finding the right switches to change cell behavior. That search has been ongoing in earnest for several decades now, digging into the biology of highly regenerative species, while manipulating the biology of mammals in search of the key, the most important points of intervention.

Fibroblasts are mesenchymal cells that account for the majority of the cellular density of the dermis and have a crucial role in wound healing. Until recently, fibroblasts were not considered to have extensive involvement in the field of scarless wound healing and were seen only as extracellular matrix (ECM) producing cells. It is now understood that there are many lineages of human fibroblasts with distinct and heterogeneous functions. Simply, some of these fibroblasts lead to scarring and some lead to regeneration. The early human foetus has mainly regenerative fibroblasts, but during aging the number of scarring fibroblasts increase to become the majority in the adult.

Scarring is the typical physiological outcome of wound healing. It is an evolutionary adaptation that provides quick and effective repair to damaged tissues, sometimes at the expense of tissue integrity and function. Scar tissue lacks skin appendages and has an organised collagen structure replacing the typical "basket-weave" dermal structure in unwounded tissues, leading to reduced tensile strength. Ideal wound repair would involve regeneration of the normal skin structure, including its associated appendages.

The ability to prevent scarring has applications beyond cosmetic and aesthetic uses, with the ability to restore function to extensively damaged tissues and preclude pathological scarring. This article describes current understanding of fibroblast heterogenicity and involvement in wound healing, focusing on the role of fibroblasts during physiological scarring. We also present the current most promising targets involving fibroblasts in the reduction of scarring and how we can manipulate the behaviour of fibroblasts to mimic the wound regeneration models in the human foetus. These targets include the pro-fibrotic EN1 positive fibroblast lineage, TGFβ1 inhibition, and genetic therapies utilising miRNAs and siRNAs.

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