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  • What is the Degree of Synergy Between Different Longevity-Associated Mechanisms?
  • α-synuclein Aggregation Impairs Autophagy in Brain Tissue
  • Another Example of a Galactose-Conjugated Senolytic Prodrug
  • A Mitochondrial Signal of Sarcopenia and Frailty Found in Small Extracellular Vesicles
  • In Search of Very Rare Genetic Variants with Large Effects on Longevity
  • The Ordering of Cholesterol Accumulation and Inflammatory Response in Foam Cell Formation
  • An Example of a Small Molecule Approach to Telomere Lengthening
  • Reducing Neuroinflammation Slows Onset of Neurodegeneration in Animal Models
  • Hydrogen Treatment Modestly Dampens Oxidative Stress in Nematodes
  • Rapamycin Slows Age-Related Periodontitis in Mice
  • Towards Ionomic Aging Clocks
  • Towards an Amyloid-β Sequestering Nanoparticle to Block Protein Aggregation
  • Improving Transplanted Stem Cell Function via Tethered Signal Molecules
  • MiR-375 and Autophagy in the Progression of Osteoarthritis
  • Correlating Structural Changes in the Hippocampus with Memory Decline

What is the Degree of Synergy Between Different Longevity-Associated Mechanisms?

The degree to which interventions that target different mechanisms associated with longevity might stack or synergize to produce greater gains is a woefully understudied topic. Study of synergies between treatment approaches is in general poorly studied and poorly developed throughout the medical biotechnology community; the incentives in place discourage this sort of work at every level of development. Funding is sparse, and different groups holding intellectual property for different approaches tend not to cooperate with one another. Thus, thirty years in to the modern study of interventions that can extend longevity in laboratory species, whether or not the scores of different approaches synergize, and to what degree, remains largely unexplored and unknown.

For what it is worth, it does seems unlikely that combining three or more marginal effects based on stress response upregulation will produce an outcome worth caring about. Equally, many of the diverse mechanisms demonstrated to modestly slow aging in animal models are just different ways of influencing the same underlying system, and shouldn’t be expected to produce synergies. Nonetheless, this area of study is criminally neglected, and this will become ever more an issue as the first narrow rejuvenation therapies are developed, approaches that repair specific forms of underlying damage that are causative of aging, and can thus produce sizable benefits. As an example of one of the few projects of recent years to focus on the foundations needed to discover and develop combinatorial therapies, researchers here establish a database of reported interactions between longevity-associated genes.


The main goal of the SynergyAge database is to host high-quality, manually curated information about the synergistic and antagonistic lifespan effects of genetic interventions in model organisms. Although our group aims to better understand human aging, data on the effect of multiple genetic manipulations in humans is inexistent (for obvious reasons). As such, SynergyAge relies on reporting combinations of genetic manipulations from model organisms only.

Currently three organisms are included, worms, flies and mice, with data curated so far coming mostly from worms. This bias is mainly due to a easier methodology of modulating gene expression in worms (e.g. through RNAi) but also due to lifespan screening in worms being much faster (worms live much less and are a friendly model for this type of studies). All entries in SynergyAge are based on experimentally validated results from peer-reviewed scientific literature and are manually extracted by our database curators.

SynergyAge: a curated database for synergistic and antagonistic interactions of longevity-associated genes

Interventional studies on genetic modulators of longevity have significantly changed gerontology. While available lifespan data is continually accumulating, further understanding of the aging process is still limited by the poor understanding of epistasis and of the non-linear interactions between multiple longevity-associated genes. Unfortunately, based on observations so far, there is no simple method to predict the cumulative impact of genes on lifespan. As a step towards applying predictive methods, but also to provide information for a guided design of epistasis lifespan experiments, we developed SynergyAge – a database containing genetic and lifespan data for animal models obtained through multiple longevity-modulating interventions.

The studies included in SynergyAge focus on the lifespan of animal strains which are modified by at least two genetic interventions, with single gene mutants included as reference. SynergyAge provides an easy to use web-platform for browsing, searching and filtering through the data, as well as a network-based interactive module for visualization and analysis.

α-synuclein Aggregation Impairs Autophagy in Brain Tissue

Age-related neurodegeneration is characterized by the aggregation of a small number of proteins, including α-synuclein, that can become altered in a manner that encourages other molecules of the same protein to alter in the same way. These altered forms of protein precipitate to form structures solid fibrils and deposits, surrounded by a halo of toxic biochemistry that impairs cell function. Today’s open access paper explores just one of the ways in which α-synuclein harms cells, in this case by downregulating the operation of autophagy.

Autophagy is the name given to a collection of cellular maintenance processes that are particularly important in long-lived cells such as the neurons of the central nervous system. Autophagy recycles damaged and unwanted structures and proteins in the cell. When it falters, cells accumulate dysfunctional components and suffer accordingly. Unfortunately, evidence suggests that the efficiency of autophagy declines with age, though the underlying causes of this issue are poorly understood. Increases in autophagy are thought to be responsible for the extension of life produced by the practice of calorie restriction, as well as many other interventions shown to improve health and extend health in

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

Parkinson’s disease (PD) is a common late onset progressive neurodegenerative disease most characterized by movement disorder resulting from the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In addition, PD is also characterized by the presence of protein inclusions known as Lewy bodies (LB) and Lewy neurites (LN), which are composed of aggregated α-synuclein (αS), in multiple neuronal populations. While the etiology of PD is unknown in most cases, αS abnormalities are mechanistically linked to PD pathogenesis as mutations in αS cause PD in a small number of familial PD pedigrees. Currently, how αS abnormalities cause neuronal dysfunction and degeneration is not fully understood. However, studies have implicated oxidative stress in the pathogenesis of PD and dysfunction in proteostasis. While oxidative stress in neurons has complex and multifaceted effects, recent reports suggest that activation of c-Abl, a non-receptor tyrosine kinase, can be stimulated by oxidative stress. And thus, may be linked to the pathogenesis of PD, Alzheimer’s disease (AD) and other neurodegenerative diseases.

c-Abl is a tyrosine kinase known to be activated by cellular stressors, such as oxidative stress and DNA damage. c-Abl also functions to regulate many fundamental cellular processes, such as cell survival, migration, and growth factor signaling. Emerging studies implicate aberrant c-Abl activity in neurodegenerative disease. In PD, c-Abl is activated in regions showing DAergic neurodegeneration, such as the striatum and SNpc, and inactivates parkin by phosphorylation. Significantly, c-Abl activation is linked to αS pathology as increased αS expression in cells and transgenic (Tg) mice was associated with c-Abl activation, and inhibition of c-Abl or the loss of c-Abl expression leads to attenuation of αS levels and/or aggregation. Some of these studies implicate c-Abl as an inhibitor of autophagy. However, it is unknown how c-Abl regulates autophagy.

We show that c-Abl-dependent inhibition of autophagy is p53 dependent, as c-Abl activation in a transgenic mouse model of α-synucleinopathy (TgA53T) and human PD cases are associated with the increased p53 activation. Significantly, active p53 in TgA53T neurons accumulates in the cytosol, which may lead to inhibition of autophagy. Further, both c-Abl and p53 activity is positively associated with mTOR activity and inversely associated with AMPK/ULK1 activity, showing that c-Abl and p53 directly impact the pathways relevant to autophagy regulation. Finally, we show that c-Abl-dependent pathway is a significant target for therapeutic intervention as pharmacological inhibition of c-Abl delays disease onset in two independent Tg mouse models of α-synucleinopathy. Our data identify a novel pathway for regulation of autophagy in α-synucleinopathy and support the development of c-Abl and p53 inhibitors for disease modifying therapies for PD and other α-synucleinopathies.

Another Example of a Galactose-Conjugated Senolytic Prodrug

Killing cells is easy. Killing only the cells that you want to kill, while leaving all other cells untouched, is very much more challenging. The ability to do this is fundamental to much of the future of medicine, however. The aging body contains many cell populations that cause significant harm and should be removed, including misconfigured T cells, age-associated B cells, precancerous cells, and of course senescent cells of many different types. Great benefits to health and longevity might be obtained via efficient means of targeting that enable therapies to only destroy unwanted, harmful cells.

This point is well illustrated by present efforts to selectively destroy senescent cells. Today’s open access paper is one of a number of recent publications that focus on using galactose conjugation to produce prodrugs that are highly selective to senescent cells. Senescent cells produce a lot of β-galactosidase, a protein that acts to strip galactose from other molecules. It is thus possible to combine any one of a range of toxic cell-killing compounds with galactose to produce molecules that are entirely innocuous until they encounter β-galactosidase, making the therapy very specific to senescent cells.

Researchers have tried this approach with the overly toxic senolytic drug navitoclax, with some success, but one really doesn’t have to be clever about the drug used. In principle any of the cytotoxic compounds employed widely in the cancer research community will work. Thus other groups have used duocarmycins, while the researchers noted here instead chose gemcitabine, and a long list of alternative options exist beyond these.

Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice

Previous studies have shown that compounds termed ‘senolytics’ could kill senescent cells. Reported senolytics target anti-apoptotic pathways, which are up-regulated to inhibit apoptosis in senescent cells. These senolytics have been reported to eliminate certain types of senescent cells and have shown the potential to improve physiological function in several tissues. However, senolytic drugs have significant limitations in killing senescent cells in terms of specificity and broad-spectrum activity because of the dynamic and highly heterogeneous nature of the senescence program, which leads to the varying sensitivity of different types of senescent cells to current senolytic drugs. To overcome these challenges, it is highly demanded to develop a new strategy that permits selectively deleting senescent cells in a wide spectrum of cell types or tissues for anti-aging interventions.

To specifically target senescent cells, we focused on one primary characteristic of senescent cells – the increased activity of lysosomal β-galactosidase, exploited as senescence-associated β-galactosidase (SA-β-gal). Notably, SA-β-gal in diverse types of senescent cells is one widely used marker for identifying senescence in vitro and in vivo, which is linked to the increased content of lysosomes. Therefore, we hypothesized that lysosomal β-gal could be utilized for the design of a galactose-modified prodrug to target senescent cells in a broader spectrum. This prodrug could be processed into a cytotoxic compound by β-gal and subsequently delete senescent cells in a specific manner, a strategy that could overcome the limitations of current senolytic drugs.

Here, we designed a new prodrug, SSK1, that was specifically cleaved by lysosomal β-gal into cytotoxic gemcitabine and induced apoptosis in senescent cells. This prodrug eliminated both mouse and human senescent cells independent of the senescence inducers and cell types. In aged mice, our compound reduced SA-β-gal-positive senescent cells in different tissues, decreased senescence- and age-associated gene signatures, attenuated low-grade chronic inflammation, and improved physical function.

While SA-β-gal is widely used as a marker of cellular senescence, its elevated activity can be found in some other cells such as activated macrophages. These SA-β-gal-positive macrophages can be harmful and have been found to accumulate in injured and aged tissues contributing to chronic inflammation. Importantly, we have shown that SSK1 decreases the number of SA-β-gal-positive macrophages in injured lungs and aged livers, which is consistent with our observation of reduced secretion of chronic inflammation-related cytokines. Therefore, eliminating macrophage accumulation by SSK1 might reduce chronic inflammation and benefit aged organisms.

A Mitochondrial Signal of Sarcopenia and Frailty Found in Small Extracellular Vesicles

Much of the signaling that passes between cells is carried in extracellular vesicles, small membrane-wrapped packages of molecules. There are numerous classes of such vesicle, varying in size, such as microvesicles and exosomes. The study of vesicles has expanded considerably in recent years, as they are much easier to work with than cells, and their use is applicable to many therapeutic goals.

For example, most cell therapies presently in use produce their benefits via the signaling that is generated by transplanted cells in the short period of time before they die. Cells can largely be replaced with extracellular vesicles in this scenario, leading to a much simpler logistic chain for the therapy. Further, extracellular vesicles can be engineered to carry specific molecules into cells, a form of vector that is easier to manufacture and manage than many of the other present options.

Diagnostics and metrics may also benefit considerably from a closer look at extracellular vesicles. Vesicles are present in blood samples, and their contents and composition is, in principle, a reflection of the state of health and aging. Senescent cells, for example, produce quite a different mix of vesicles and vesicle contents in comparison to normal cells. In the same way that biomarkers are constructed from DNA methylation and protein levels, extracellular vesicle analysis may present another path to assays that can quantitatively assess the progression of aging and disease.

Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

Advancing age is associated with declining muscle mass, function, and strength, a condition referred to as sarcopenia which increases the risk of incurring negative health-related outcomes. No effective pharmacological treatments are currently available to prevent, delay, or treat sarcopenia, which is mostly due to the incomplete knowledge of the underlying pathophysiology. To further complicate the matter, at the clinical level, sarcopenia shows remarkable overlap with frailty, a “multidimensional syndrome characterized by a decrease in physiological reserve and reduced resistance to stressors”, often envisioned as a pre-disability condition. Hence, the two conditions have been merged into a new entity, referred to as physical frailty and sarcopenia (PF&S).

Mitochondrial dysfunction and sterile inflammation are invoked among the pathogenic factors of PF&S. Derangements at different levels of the mitochondrial quality control machinery have been reported in older adults with PF&S. However, whether and how cell-based alterations may spread at the systemic level and impact muscle homeostasis is presently unknown. One of the mechanisms by which cells communicate with each other involves a conserved delivery system based on the generation and release of extracellular vesicles (EVs). This shuttle system also contributes to degradative pathways responsible for eliminating oxidized cell components, including mitochondria, by establishing inter-organelle contact sites. As such, the generation and release of mitochondrial-derived vesicles (MDVs) may represent a complement to mitochondrial quality control systems.

Cell-free mitochondrial DNA (mtDNA) has been identified among the molecules released within exosomes that may act as damage-associated molecular patterns (DAMPs). However, whether and how this mechanism is in place in the setting of PF&S is unexplored. In the present study, we purified small extracellular vesicles (sEVs) from older adults with and without PF&S, quantified their amount, and characterized their content for the presence of mitochondrial components. Our results show a greater amount of sEVs in serum of PF&S participants compared with non-PF&S controls. A lower protein expression of CD9 and CD63 was found in the exosome fraction purified from participants with PF&S. These observations are in keeping with the heterogenous composition of exosomes themselves, likely reflecting a different vesicle trafficking regulation.

Lower levels of the mitochondrial components ATP5A (complex V), NDUFS3 (complex I), and SDHB (complex II) were found in participants with PF&S. With the intent of preserving mitochondrial homeostasis, mitochondrial hyper-fission segregates severely damaged or unnecessary organelles that are subsequently disposed via mitophagy. However, mitochondrial-lysosomal crosstalk may dispose mildly oxidized mitochondria via MDV release. Such a mechanism may therefore restore mitochondrial homeostasis before whole-sale organelle degradation is triggered. Though, in the case of defective mitophagy or disruption of the mitochondrial-lysosomal axis, accrual of damaged mitochondria, misfolded proteins, and lipofuscin may occur as a result of inefficient cellular quality control. Therefore, the increased sEV secretion in participants with PF&S might reflect the cell’s attempt to extrude dysfunctional mitochondria. However, the reduced secretion of MDV in the same participant group may indicate that mitochondrial quality control is impaired or that the damage to mitochondria is too severe to be disposed via MDVs.

In Search of Very Rare Genetic Variants with Large Effects on Longevity

Genetic studies of the past twenty years have quite effectively ruled out the idea that genetic variation has a meaningful impact on life span in the overwhelming majority of people. To a first approximation, there are no longevity genes. Rather there is a mosaic of tens of thousands of tiny, situational, interacting effects, that in aggregate produce an outcome on health that is far smaller than the results of personal choice in health and lifestyle. Near the entirety of the effects that your parents have on your health and life span stems from their influence on the important choices – whether you smoke, whether you get fat, whether you exercise.

But this is not to say that there are no longevity genes. It only constrains our expectations on their rarity, just as human demographics constrains our expectations on how large an effect size is plausible. Big databases and modern data mining can still miss rare variants and mutations. There is the example of the single family of PAI-1 loss of function mutants who might live seven years longer than their peers – possibly as a result of the influence of PAI-1 on the burden of cellular senescence. One might also suspect that the exceptional familial longevity of some Ashkanazi Jews is simply too much for good lifestyle choice to explain, though there no single variant really stands out after many years of assessment.

The commentary here notes recent research into rare variants and life span that, once again, fails to find a sizable contribution to longevity or its inheritance. At some point, we must accept that genetics is most likely not a direct and easy path to enhanced human longevity. It is an important tool in the toolkit, enabling therapies for a range of uses, but the goal of a modest adjustment to a few genes that produces an altered metabolism that yields significant gains in longevity (with minimal side-effects) may be a mirage. Time will tell.

Aging: Searching for the genetic key to a long and healthy life

For centuries scientists have been attempting to understand why some people live longer than others. Individuals who live to an exceptional old age – defined as belonging to the top 10% survivors of their birth cohort – are likely to pass on their longevity to future generations as an inherited genetic trait. However, recent studies suggest that genetics only accounts for a small fraction (~10%) of our lifespan. One way to unravel the genetic component of longevity is to carry out genome-wide association studies (GWAS) which explore the genome for genetic variants that appear more or less frequently in individuals who live to an exceptional old age compared to individuals who live to an average age. However, the relatively small sample sizes of these studies has made it difficult to identify variants that are associated with longevity.

The emergence of the UK Biobank – a cohort that contains a wide range of health and medical information (including genetic information) on about 500,000 individuals – has made it easier to investigate the relationship between genetics and longevity. Although it is not yet possible to study longevity directly with the data in the UK Biobank, several GWAS have used these data to study alternative lifespan-related traits, such as the parental lifespan and healthspan of individuals (defined as the number of years lived in the absence of major chronic diseases). These studies have been reasonably successful in identifying new genetic variants that influence human lifespan, but these variants can only explain ~5% of the heritability of the lifespan-related traits.

The GWAS have only focused on relatively common genetic variants (which have minor allele frequencies (MAFs) of ≥1%), and it is possible that rare variants might be able to explain what is sometimes called the ‘missing heritability’. Now researchers report how they analyzed data from the UK Biobank and the UK Brain Bank Network (which stores and provides brain tissue for researchers) to investigate how rare genetic variants affect lifespan and healthspan.

One type of rare genetic variant, called a protein-truncating variant, can dramatically impact gene expression by disrupting the open reading frame and shortening the genetic sequence coding for a protein. The team calculated how many of these rare protein-truncating variants, also known as PTVs, were present in the genome of each individual, and found ultra-rare PTVs (which have MAFs of less than 0.01%) to be negatively associated with lifespan and healthspan. This suggests that individuals with a small number of ultra-rare PTVs are more likely to have longer, healthier lives. This work is the first to show that rare genetic variants play a role in lifespan-related traits, which is in line with previous studies showing rare PTVs to be linked to a variety of diseases. However, these variants only have a relatively small effect on human lifespan and cannot fully explain how longevity is genetically passed down to future generations.

The Ordering of Cholesterol Accumulation and Inflammatory Response in Foam Cell Formation

The development of atherosclerotic lesions involves the dysfunction of macrophage cells. They are normally responsible for removing lipids from lesions and handing it off to HDL particles to be returned to the liver, but the presence of oxidized lipids causes them to become inflammatory foam cells, packed with lipids and eventually dying to add their mass to the growing lesion. Researchers here study the formation of foam cells in order to better understand the ordering of events. At present the more promising new lines of therapy for atherosclerosis involve ways to make macrophages resilient to the foam cell fate, such as via removal of oxidized lipids. These are still in comparatively early stages of development, however.

Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size.

To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes.

We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

An Example of a Small Molecule Approach to Telomere Lengthening

Research groups are eyeing telomere lengthening as a way to improve stem cell function. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little of their length is lost with each cell division, and cells with very short telomeres become senescent or self-destruct. In the vast majority of cells in the body, this is an important part of the Hayflick limit on cellular replication. Stem cells, however, use telomerase to extend their telomeres.

With age average telomere length is reduced. In most cells, this is just a reflection of the balance between the activity of stem cells, delivering new daughter cells with long telomeres, and ongoing cellular replication that shortens telomeres. As stem cell function declines with age, it isn’t surprising to see average telomere length decline. In stem cells themselves, however, the situation is more complex. Why exactly they decline in function, and why extending telomeres improves that function, is far from settled. As outlined here, researchers are investigating the regulation of telomere length in stem cells in order to find targets that might lengthen these telomeres and thus improve stem cell function. This might be a safer approach to achieving most of the same goals of telomerase gene therapy, but without the concerns about side-effects that might result from to expression of telomerase throughout tissues.

A new study may offer a breakthrough in treating dyskeratosis congenita (DC) and other so-called telomere diseases, in which cells age prematurely. Using cells donated by patients with the disease, researchers identified several small molecules that appear to reverse this cellular aging process. The compounds identified in the study restore telomeres, protective caps on the tips of our chromosomes that regulate how our cells age. Telomeres consist of repeating sequences of DNA that get shorter each time a cell divides. The body’s stem cells, which retain their youthful qualities, normally make an enzyme called telomerase that builds telomeres back up again. But when telomeres can’t be maintained, tissues age before their time. A spectrum of diseases can result.

DC can be caused by mutations in any of multiple genes. Most of these mutations disrupt telomerase formation or function – in particular, by disrupting two molecules called TERT and TERC that join together to form telomerase. TERT is an enzyme made in stem cells, and TERC is a so-called non-coding RNA that acts as a template to create telomeres’ repeating DNA sequences. Both TERT and TERC are affected by a web of other genes that tune telomerase’s action. One of these genes is PARN, important for processing and stabilizing TERC. Mutations in PARN mean less TERC, less telomerase, and prematurely shortened telomeres.

Researchers focused on an enzyme that opposes PARN and destabilizes TERC, called PAPD5. The team first conducted large-scale screening studies to identify PAPD5 inhibitors, testing more than 100,000 known chemicals. They got 480 initial “hits,” which they ultimately narrowed to a small handful. They then tested the inhibitors in stem cells made from the cells of patients with DC. The compounds boosted TERC levels in the cells and restored telomeres to their normal length. The team then introduced DC-causing PARN mutations into human blood stem cells, transplanted those cells into mice, then treated the mice with oral PAPD5 inhibitors. The compounds boosted TERC and restored telomere length in the transplanted stem cells, with no adverse effect on the mice or on the ability to form different kinds of blood cells.

In the future, researchers hope to validate PAPD5 inhibition for other diseases involving faulty maintenance of telomeres – and perhaps even aging itself. “We envision these to be a new class of oral medicines that target stem cells throughout the body. We expect restoring telomeres in stem cells will increase tissue regenerative capacity in the blood, lungs, and other organs affected in DC and other diseases.”

Reducing Neuroinflammation Slows Onset of Neurodegeneration in Animal Models

Alzheimer’s disease is strongly driven by chronic inflammation in brain tissue. Studies in which senescent, inflammatory microglia are removed from the brain strongly suggests this to be the case in the later stages of the condition. Here, researchers use animal models to demonstrate that it may also be the case in the early stages, prior to onset of obvious symptoms of cognitive decline. A view of Alzheimer’s disease in which inflammation is the dominant mechanism – resulting from some combination of exposure to pathogens, accumulation of senescent cells, and dysregulation of immune cells due to amyloid-β aggregates – is gathering support these days.

In a new animal study examining Alzheimer’s disease, researchers found that disease progression could be slowed by decreasing neuroinflammation in the brain before memory problems and cognitive impairment were apparent. The new findings point to the importance of developing therapies that target very early stages of the disease. In 2011, the National Institute on Aging updated the diagnostic criteria for Alzheimer’s disease to reflect its progressive nature. The criteria added a preclinical stage during which brain changes are taking place, but the person is still asymptomatic and, therefore, unaware of his condition. Biomarker profiles could eventually be used to identify people in the disease’s early stages who might benefit from early treatments.

“Starting an intervention at the earliest stage of the disease, when cellular and molecular alterations have already been triggered but major damage to the brain has not yet occurred, could offer a way to reduce the number of people who go on to develop full Alzheimer’s dementia. However, there have been few studies in animals examining therapeutic strategies that target timepoints before symptoms can be seen.”

The researchers designed an animal study to gain a deeper understanding of the role of neuroinflammation in Alzheimer’s disease during the pre-symptomatic stage of the disease, which might represent the best time for therapeutic intervention. The study results suggest that rebalancing neuroinflammation in animals that show altered neuroinflammatory parameters could be beneficial. “Our results help demonstrate that neuroinflammation in Alzheimer’s disease is an extremely complex phenomenon that can change over the disease’s progression and varies based on factors such as affected brain area. We hope that these findings will prompt scientists to further investigate neuroinflammation at the earliest stages of the disease, which may represent an important pharmacological target.”

Hydrogen Treatment Modestly Dampens Oxidative Stress in Nematodes

Hydrogen can scavenge free radical molecules, and thus act as a form of antioxidant. Researchers here demonstrate that in action in nematode worms. Excessive levels of free radicals such as reactive oxygen species are present in older individuals, and this state of oxidative stress contributes to cell and tissue dysfunction. The role of oxidants is a complicated one, however, as they serve as signals to cellular maintenance processes. Alteration in amounts of oxidative stress frequently have counterintuitive results on health and longevity in short-lived laboratory species. Further, the size of the effect in species such as the nematodes used here is small enough that one would expect there to be little benefit to long-lived species such as our own, given that benefits to longevity from all interventions that affect cellular maintenance signaling scale down as species life span increases.

It is well known that hydrogen can effectively scavenge free radicals in vivo or in vitro and exhibit valuable antioxidant activity. Under stress such as ischemia or hypoxia in the brain, heart and other vital organs and tissues, immune cells release a large amount of reactive oxygen species (ROS), while hydrogen can selectively neutralize hydroxyl radicals and peroxynitrites, which are related to the activation of the Nrf2 signaling pathway. Hydrogen-rich saline (HRS) can also reduce the damage to important organs, tissues, and cells caused by oxidative stress. In general, hydrogen has two advantages compared with other antioxidants, such as vitamin A and vitamin C. First, hydrogen can selectively neutralize hydroxyl radicals and nitrite anions. Second, it can quickly reach the area in danger regardless of cellular barrier. The fact that antioxidants have limited therapeutic success may be because most antioxidants cannot reach specific ROS-abundant regions. Thus, hydrogen can be used as an effective antioxidant therapy owing to its ability to diffuse rapidly across cellular membranes, because it can reach and react with cytotoxic ROS and protect against oxidative damage.

The free radical aging theory, which is also called the aging oxidative stress theory, states that aging is caused by normal oxidative metabolism by-products such as ROS. Normally, the antioxidant defense system eliminates ROS, and living organisms are protected from oxidative stress. Therefore, weakening of the antioxidant defense system, which may be caused by several factors, such as aging, will lead to excess oxidative stress and senescence. The detection of hydrogen peroxide (H2O2) further suggests that aging is caused by excess ROS. In C. elegans, genes such as sod-1, sod-4, and sod-5 encode Cu/Zn-SODs, and sod-2 and sod-3 encode Fe/Mn-SODs. Therefore, mutations in sod family genes may impact defense against oxidative stress. In this study, we found that older nematodes have higher ROS levels. Interestingly, after hydrogen treatment, the ROS levels were significantly decreased, and hydrogen could significantly extend the lifespans of the N2, sod-3 and sod-5 mutant strains, by approximately 22.7%, 9.5%, and 8.7%, respectively.

In addition, aging is regulated by a variety of pathways, such as the insulin signaling pathway, the rapamycin target signaling pathway, and the caloric restriction pathway. However, our results showed that the lifespans of the daf-2 and daf-16 strains, in which these pathways are upregulated, were not affected after hydrogen treatment. Based on these data and previous reports that hydrogen is a valuable antioxidant in vitro, lifespan extension by hydrogen is mostly related to ROS levels. It seemed that exogenous hydrogen does not act through the insulin signaling pathway to produce its antiaging effects, which may result from a direct reaction with ROS in vivo.

Rapamycin Slows Age-Related Periodontitis in Mice

The mTOR inhibitor rapamycin slows the progression of aging in mice. The may largely be a result of upregulated autophagy, as is the case for many other means of slowing aging in short-lived species, including calorie restriction. If an intervention slows aging generally, the odds are fairly good that any specific aspect of aging will also be slowed. Here, researchers show that rapamycin treatment improves the outlook for age-related periodontitis in mice.

Periodontal disease, also known as gum disease, is a common problem in older adults that causes painful inflammation, bone loss, and changes in the good bacteria that live in the mouth. Yet there are no treatments available beyond tooth removal and/or having good oral hygiene. Rapamycin is an immune-suppressing drug currently used to prevent organ rejection in transplant recipients. Previous studies in mice have also suggested that it may have life-extending effects, which has led to interest in studying the drug’s effects in many age-related diseases.

To find out if rapamycin might slow periodontal disease, researchers added the drug to the food of middle-aged mice for eight weeks and compared their oral health with untreated mice of the same age. Similar to humans, mice also experience bone loss, inflammation, and shifts in oral bacteria as they age. Using a 3D-imaging technique called micro-computed tomography, the team measured the periodontal bone, or bone around the tooth, of the rapamycin-treated and untreated mice. They showed that the treated mice had more bone than the untreated mice, and had actually grown new bone during the period they were receiving rapamycin.

The work also showed that rapamycin-treated mice had less gum inflammation. Genetic sequencing of the bacteria in their mouths also revealed that the animals had fewer bacteria associated with gum disease and a mix of oral bacteria more similar to that found in healthy young mice. While rapamycin is already used to treat certain conditions, it can make people more susceptible to infections and may increase their risk of developing diabetes, at least at the higher chronic doses typically taken by organ transplant patients. Clinical trials in humans are needed to test whether rapamycin’s potential oral health and other benefits outweigh its risks.

Towards Ionomic Aging Clocks

The ionome is the elemental composition of a tissue, organ, or individual. This composition changes over the course of aging, and may do so in ways that allow the production of an aging clock, a measure of chronological or physiological age. This line of development adds to work on the well-known epigenetic clocks, proteomic clocks, and other assessments of age constructed from algorithmic compositions of simple biomarkers. At the end of the day, all of these approaches need a great deal more validation if they are to be used as originally intended, as a way to rapidly assess potential rejuvenation therapies and thus speed up the field. Since it remains quite unclear as to what exactly these clocks measure, meaning which processes of aging cause the clock numbers to change, the results are not yet actionable.

Aging involves coordinated yet distinct changes in organs and systems throughout life, including changes in essential trace elements. However, how aging affects tissue element composition (ionome) and how these changes lead to dysfunction and disease remain unclear. Here, we quantified changes in the ionome across eight organs and 16 age groups of mice. This global profiling revealed novel interactions between elements at the level of tissue, age, and diet, and allowed us to achieve a broader, organismal view of the aging process. We found that while the entire ionome steadily transitions along the young-to-old trajectory, individual organs are characterized by distinct element changes.

The ionome of mice on calorie restriction (CR) moved along a similar but shifted trajectory, pointing that at the organismal level this dietary regimen changes metabolism in order to slow down aging. However, in some tissues CR mimicked a younger state of control mice. Even though some elements changed with age differently in different tissues, in general aging was characterized by the reduced levels of elements as well as their increased variance. The dataset we prepared also allowed to develop organ-specific, ionome-based markers of aging that could help monitor the rate of aging. In some tissues, these markers reported the lifespan-extending effect of CR. These aging biomarkers have the potential to become an accessible tool to test the age-modulating effects of interventions.

Towards an Amyloid-β Sequestering Nanoparticle to Block Protein Aggregation

Researchers here report on development of a nanoparticle that sweeps up the amyloid-β associated with Alzheimer’s disease, preventing it from forming aggregates. When stuck to the nanoparticle, amyloid-β will not generate the harmful biochemistry that arises as a consequence of the formation of aggregated protein structures. This is an interesting approach to reducing levels of amyloid-β, albeit at a very early stage in development. As always, one must note that there is considerable debate over whether amyloid-β clearance is either the right approach to Alzheimer’s disease, or sufficient in and of itself to prevent pathology. Amyloid-β aggregation is clearly harmful, the evidence is plentiful on that front, but it is possible that its presence is a side-effect of a more dominant disease mechanism, such as, for example, chronic inflammation derived from persistent infection.

People who are affected by Alzheimer’s disease have a specific type of plaque, made of self-assembled molecules called β-amyloid (Aβ) peptides, that build up in the brain over time. Researchers have developed an approach to prevent plaque formation by engineering a nano-sized device that captures the dangerous peptides before they can self-assemble. The researchers covered the surface of the new nanodevice with fragments of an antibody that recognizes and binds to the Aβ peptides. The surface of the nanodevice is spherical and porous, and its craters maximize the available surface area for the antibodies to cover. More surface area means more capacity for capturing the sticky peptides.

A full antibody molecule can be up to a few dozen nanometers long, which is big in the realm of nanotechnology. However, only a fraction of this antibody is involved in attracting the peptides. To maximize the effectiveness and capacity of the nanodevices, researchers produced tiny fragments of the antibodies to decorate the nanodevice’s surface. The scientists constructed the base of the porous, spherical nanodevices out of silica, a material that has long been used in biomedical applications due to its flexibility in synthesis and its nontoxicity in the body. Coated with the antibody fragments, the nanodevices capture and trap the Aβ peptides with high selectivity and strength.

The scientists tested the effectiveness of the devices by comparing how the peptides behaved in the absence and presence of the nanodevices. These studies supported the case that the nanodevices sequester the peptides from the pathway to aggregation by more than 90 percent compared to the control silica particles without the antibody fragments. However, the devices still needed to demonstrate their effectiveness and safety within cells and brains.

Improving Transplanted Stem Cell Function via Tethered Signal Molecules

The field of biotechnology is churns with inventive technology demonstrations; this is an era of creativity, unleashed by a rapid advance in knowledge and capabilities. Here, researchers are presented with the challenge of achieving sustained beneficial activation of transplanted stem cells, where culturing the cells with activating signal molecules prior to transplantation produces only a transient effect. They solve the problem by tethering the signal molecules to the stem cell surfaces; the transplanted cells will continue to be stimulated by this signal for as long as they survive. Like all of the best ideas, it is entirely obvious, but only in hindsight.

Muscle ischemia, or damage to muscle from limited oxygen or blood supply, can result from multiple causes, such as injury to a limb or peripheral artery disease. Stem cells derived from a patient’s own fat tissue are known to produce factors that prompt new blood vessels to grow into the damaged muscle, restoring oxygen and nutrients, and to modulate inflammation in the damaged tissues. However, in vivo experiments have shown limited benefits, as the stem cells’ activity seems to decline after injection into the muscle.

A molecule naturally produced in the body called tumor necrosis factor alpha can spur the stem cells to secrete more of the desired factors. Other studies have tried incubating the cells with TNF-alpha before injection, but the effects fade quickly. Researchers decided to try tethering the TNF-alpha directly to the stem cells, creating nanostimulators – nanoparticles laced with TNF-alpha. The nanoparticles bind to a receptor on the surface of the stem cells, providing localized, targeted, and extended delivery of TNF-alpha.

The researchers tested their approach on mice with surgically induced ischemia in one of their hind legs. They isolated the stem cells from fat tissue, mixed them with the nanostimulators and injected them locally to the mice’s affected legs. The researchers saw increased blood flow and oxygen levels in the ischemic legs. They also witnessed improvements in mobility – the treated mice could walk longer distances and their legs were stronger.

MiR-375 and Autophagy in the Progression of Osteoarthritis

Much of the work that the research community conducts on age-related disease is similar to the example here: attempting to pick apart the proximate causes of pathology in an altered, aged, diseased cellular metabolism. This is far removed from root causes, and thus presents only limited options for the development of beneficial therapies. The biochemistry of any age-related disease is enormously complex in its details, and manipulating any one part of it still leaves all of the rest to progress and cause issues. Since age-related diseases are the downstream result of a less complex set of root causes, it makes much more sense to investigate the root causes. Unfortunately, this remains a comparatively unpopular strategy in the research community.

Osteoarthritis (OA) is a disease with high morbidity, which mainly afflicts the weight-bearing joints, such as the hips and knees, and causes physical disability. However, the precise pathogenesis of OA has not been detailed completely. Research showed that chondrocyte autophagy, as a self-protective mechanism, has been considered as a potential target for recuperating chondrocytes viability and then suppressing the progression of OA. Cellular dysfunction and death often occur when the capacity of endoplasmic reticulum could not bear the protein folding under prolonged endoplasmic reticulum stress (ERs). Hence, the occurrence of ERs would aggravate OA severity. The effects of autophagy and ERs on osteoarthritis remain to be further explored.

MicroRNAs (miRNAs) have been suggested to participate in regulating gene expression after transcription in OA. These small regulators serve vital function in various biological processes. Accumulating research has suggested that some miRNAs had regulatory effect in the formation and process of OA. For instance, miR-155 inhibits autophagy in chondrocytes by regulating autophagy proteins expression. MiR-375 was also found to be connected with cell autophagy. However, few researchers have explored the role of miR-375 in OA.

In the current research, we analyzed the differentially expressed mRNAs and miRNAs between OA and normal cartilage tissues by analyzing microarray datasets. In human samples, we discovered that miR-375 was overexpressed in OA, while ATG2B was conspicuously down-regulated in pathological OA articular cartilage tissues. In vitro, miR-375 inhibited autophagy and enhanced ERs of chondrocytes by suppressing the expression of ATG2B. Simultaneously, apoptosis of chondrocytes was promoted by miR-375 mimics. Furthermore, OA mice model induced by destabilization of the medial meniscus (DMM) surgery in the right knee was established and verified the function of miR-375 on exacerbating OA. Therefore, miR-375 could be a potential target for OA treatment.

Correlating Structural Changes in the Hippocampus with Memory Decline

Memory function declines with age. Some part of this is the result of outright structural damage in the brain, caused by the periodic rupture of small blood vessels that kills a small volume of tissue – a form of damage that proceeds that much more rapidly in hypertensive individuals, for all of the obvious reasons. But this is far from the only form of structural change in the brain. More subtle processes of damage and adaptation to damage also take place. Researchers here assess what can be done with modern tools in order to correlate structural change with cognitive decline.

Aging, even in the absence of clear pathology of dementia, is associated with cognitive decline. Neuroimaging, especially diffusion-weighted imaging, has been highly valuable in understanding some of these changes in live humans, non-invasively. Traditional tensor techniques have revealed that the integrity of the fornix and other white matter tracts significantly deteriorates with age, and that this deterioration is highly correlated with worsening cognitive performance. However, traditional tensor techniques are still not specific enough to indict explicit microstructural features that may be responsible for age-related cognitive decline and cannot be used to effectively study gray matter properties.

Here, we sought to determine whether recent advances in diffusion-weighted imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI) and Constrained Spherical Deconvolution, would provide more sensitive measures of age-related changes in the microstructure of the medial temporal lobe. We evaluated these measures in a group of young (ages 20-38 years old) and older (ages 59-84 years old) adults and assessed their relationships with performance on tests of cognition.

We found that the fiber density (FD) of the fornix and the neurite density index (NDI) of the fornix, hippocampal subfields, and parahippocampal cortex, varied as a function of age in a cross-sectional cohort. Moreover, in the fornix and hippocampal subields DG/CA3 and CA1, these changes correlated with memory performance, even after regressing out the effect of age, suggesting that they were capturing neurobiological properties directly related to performance in this task.

These measures provide more details regarding age-related neurobiological properties. For example, a change in fiber density could mean a reduction in axonal packing density or myelination, and the increase in NDI observed might be explained by changes in dendritic complexity or even sprouting. These results provide a far more comprehensive view than previously determined on the possible system-wide processes that may be occurring because of healthy aging and demonstrate that advanced diffusion-weighted imaging is evolving into a powerful tool to study more than just white matter properties.