As of 2023, the flagship research program at LEVF is our Robust Mouse Rejuvenation (RMR) studies, the first of which (RMR-1) was initiated in early 2023. In this program, we seek to investigate the potential lifespan-enhancing effects of combining multiple interventions in middle-aged mice which have been previously shown to extend the lifespans of lab mice. For RMR-1, we decided to test a senolytic intervention as one of the four interventions administered in combination to our study mice at Ichor Life Sciences. Those four interventions are: (a) Senescent cell ablation via galactose-conjugated Navitoclax ("Nav-Gal"); (b) Rapamycin in food at 42 ppm; (c) Enhanced telomerase expression via repeated TERT gene therapy (via nasally administered AAV-mTERT); (d) Hematopoietic stem cell transplantation. In this essay, we hope to answer readers' questions about the role of cellular senescence in aging and the role of senolytic therapies in rejuvenation. We will further speculate on how reducing the burden of senescent cells might synergize with other rejuvenation therapies.

The word senolytics is a blend of two words - senescence and lysis. Lysis means "a process of disintegration or dissolution". So, the use of senolytics is an effort to selectively and deliberately induce disintegration or elimination of senescent cells. One could reasonably want to be cautious about purposefully inducing the death of cells in the body, but there have been multiple reports of health benefits associated with administration of senolytics, particularly when done in animals with elevated senescent cell burden such as animals that are older or have been treated with chemotherapy or radiation - both of which are known to elevate the prevalence of senescent cells. There appear to be multiple mechanisms by which senolysis can be accomplished. The most common mechanism is to inhibit proteins associated with cell survival during stressful situations. The survival of senescent cells is dependent on proteins and processes that are different than those used for survival by non-senescent cells. We can exploit these differences to specifically target senescent cells while leaving non-senescent cells relatively unaffected.

We found Navitoclax, also called ABT-263, particularly interesting for our first RMR study for several reasons. First, Navitoclax appears to be effective at inhibiting Bcl-2, Bcl-w, and Bcl-XL. Because different cell types can overexpress different survival proteins when they become senescent, the ability of Navitoclax to inhibit all three of these proteins means that it might be relatively more effective at reducing the elevated numbers of senescent cells in many different tissues in the body. Second, Navitoclax also seems to be increasingly well studied. There have been many scientific reports about its effects on both normal and senescent cells, and this gives us confidence about its possible effects in older animals. However, Navitoclax has a drawback: it has been shown to be toxic to normal, healthy platelets and other immune cells. Fortunately, some researchers have designed a method to substantially reduce the toxicity of Navitoclax to non-senescent cells. Attaching galactose to Navitoclax reduced the toxicity of Navitoclax for normal cells but retained its toxicity for senescent cells, as senescent cells contain a lot of beta-galactosidase, an enzyme that cleaves galactose molecules from the other molecules they are attached to.

There is evidence that a persistent, elevated prevalence of senescent cells inhibits wound healing, immune function, tissue maintenance, and possibly stem cell function, and that these effects might limit the lifespans of aged mice (and we suspect, humans). We imagine that the elimination of senescent cells will enable the more anabolic interventions - such as TERT gene therapy and hematopoietic stem cell (HSC) transplantation - to work more effectively. Particularly in the case of HSC transplantation, we suspect that ridding the body of excessive senescent cells and senescence-associated secretory phenotype (SASP) signaling might enable those transplanted HSC to function better than they otherwise would. For example, consider the case of the bone marrow, which houses both mesenchymal stem cells (MSC) and HSCs. There is some evidence that mesenchymal stem cells become senescent during aging and secrete proteins which alter the bone marrow microenvironment, which in turn impairs HSC function. We imagine that a senolytic intervention which reduces the prevalence of senescent MSCs in the bone marrow could enhance HSC function, which includes the generation of red blood cells and immune cells.

In addition, there is some evidence to suggest that rapamycin and senescent cell ablation might be synergistic. This comes from evidence that rapamycin inhibits a protein complex called mTOR and upregulates autophagy - a process by which tissues and cells recycle their molecular materials. A study found that senescent cells seem to upregulate autophagy, but then also upregulate mTOR to survive the upregulated autophagy. It may be that inhibiting mTOR and enhancing autophagy (both accomplished by rapamycin) might facilitate greater senolysis by making senescent cells more susceptible to cell death - they might experience elevated autophagy and will fail to survive it when pro-survival mTOR is inhibited by rapamycin. So, we'll be looking for this interaction between rapamycin and senolytics and should be evident by a greater reduction in senescent cell prevalence in the mice administered both a senolytic and rapamycin, relative to mice administered a senolytic alone.

About a year ago, members of the editorial board of Biogerontology were requested to respond to a query by the editor-in-chief of the journal as to what one question within their field of ageing research still needs to be asked and answered. During the following couple of months, a majority of the editorial board members responded with their precise, and sometimes not-so-precise, questions, ideas and opinions. Based on those responses, this editorial article is my attempt to identify and compile a list of knowledge gaps in the biology of ageing research, and these are arranged under three main and general categories: (1) evolutionary aspects of longevity; (2) biological survival and death aspects; and (3) heterogeneity in ageing progression and phenotype. The implications of these knowledge gaps in biogerontology, especially in the context of ageing interventions for human health and longevity, are also discussed.

1. What are the evolved public (universal) and private (species-specific) longevity assurance genes for the essential lifespan of a species?

2. What is the nature of imperfections that limit the optimal functionality of the longevity assurance processes, and are they sex-specific?

3. With almost identical physical-time scales at the level of metabolic processes, how is the passage of biological-time regulated from one biological stage to the next through the life-cycle and until death?

4. What are the quantitative and qualitative features of the homeodynamic space in terms of the health and survival ability of a biological system?

5. What determines heterogeneity in the rate and extent of age-related changes at various levels of biological organization, from molecules to the whole body and population levels?

6. How to distinguish between harmful, useful, and neutral changes occurring during ageing?

7. How to identify and quantify the ability to tolerate, adapt, compensate and bypass age-related changes?

Since ageing is primarily a progressive loss of health, the focus of interventional strategies requires a shift from the treatment and prevention of diseases to the maintenance, recovery and enhancement of health. Such trends can already be seen emerging and being adopted.

Aging and neurodegenerative disorders are complex medical conditions with poorly understood underlying pathophysiology that may affect virtually all tissues and organs. A limited number of genes and their transcripts have been associated with either premature aging, as seen in progeria, or with longevity. The α-Klotho protein, first identified in mice studies in 1997, primarily functions as a co-receptor for fibroblast growth factor 23 (FGF23) in the kidneys and parathyroid gland and therefore has a crucial role in phosphate homeostasis, vitamin D metabolism, and vascular calcification. In addition, α-Klotho has been identified in a wide variety of tissues, consistent with its role in the aging process, including endocrine organs, arteries, and reproductive, epithelial, and neuronal tissue.

β-Klotho is primarily expressed in the liver, adipose tissue, and kidneys and plays a role in lipid and energy metabolism by acting as co-receptor for FGF15 and FGF21, while the γ-Klotho isoform is expressed in the brown adipose tissue, skin and kidneys with as yet poorly defined roles and by acting as co-receptor for FGF receptor 1b (FGFR1b), FGFR1c, FGFR2c and FGFR4 and are not discussed in the current review, which is focused on α-Klotho.

Nevertheless, preclinical studies conducted on Klotho knockout mice have revealed that Klotho deficiency is associated with impaired cognition, shorter lifespan, cardiac hypertrophy, vascular calcification, multi-organ atrophy, and fibrosis and growth retardation. Moreover, overexpression of the Klotho gene has been shown to lengthen lifespan in mice, which raises the potential question of whether Klotho may be utilized as a target to control or reverse aging and/or neurodegeneration. One drawback of such models is the lack of distinction between soluble and transmembrane Klotho molecules, which may potentially have distinct physiological roles in the human body. Whether such physiological and pathological outcomes of Klotho deficiency and/or overexpression may simply be attributable to the role of Klotho on phosphate metabolism is unclear and should be evaluated with caution with the discovery of multiple phosphate metabolism-independent functions of Klotho protein.

In this narrative review, our aim is to evaluate the potential pathophysiological and therapeutic role of Klotho protein in aging and neurodegenerative conditions. Emerging clinical and experimental insights suggest Klotho deficiency not only as a risk factor, but also a modifiable therapeutic target. Even though there is a clear need for future large-scale human studies in order to develop clinical and therapeutic strategies involving Klotho proteins in humans, this field appears to be promising.

After spending about a decade in this field, are you now more optimistic or more pessimistic than you were in the beginning?

I think I'm a mixture of things. Scientifically, the last decade has been perhaps even more incredible than the decade that preceded it. The Hallmarks of Aging paper came out in 2013. It has provided a rallying point for geroscience and became one the most cited biology papers ever. We've seen many incredible things, like actual treatments progressing. We've got senolytics now, a whole class of treatments that simply didn't exist when I first started looking into longevity. We've got epigenetic reprogramming. We'd used it for individual cells, but we now have evidence that it can potentially improve aging in whole organisms. All those interventions are super exciting. The science is progressing. The respect in which I'm less optimistic is that making the case for longevity hasn't moved on as far. Yes, there has been some increase in public perception and longevity is a real buzzword, but the ways people get exposed to it are less than ideal.

Many of them come across news stories about incredibly rich people doing a variety of, frankly, quite strange interventions to try and extend their lifespan. If this is people's first exposure to aging biology, and they might start thinking that this is some kooky pastime for gajillionaires that isn't for the likes of you and me. They don't realize that a lot of what we're talking about is drugs that could cost pennies per pill while making all of us live healthier, longer lives without having to go to bed at a very prescribed time every night and do four hours of exercise a day and only eat the same food every single day and so on.

Another challenge is that although longevity and preventative medicine have really increased in their prominence, when you talk about this in policymaking circles, so much of that discussion focuses on diet, exercise, and other lifestyle stuff. While those things are very important, and I am a huge supporter of public health, I think that it's not as important as dramatically increasing the amount of money we spend researching aging. That's because while we know that you can add a decade of life by going from the least to the most healthy dietary patterns and so on, the potential of aging biology vastly outstrips that.

If you drill down to what goes into aging biology per se, it's about 350 million a year. And this is for studying a process that kills 85% of Americans and is by far the largest cause of suffering in the United States. It just seems wildly disproportionate. Although it's very exciting to see a lot of private funding come into the field, this is still a drop in the ocean compared to US healthcare spending, which is four trillion - not four billion, but four trillion every single year. Just think about the economic impact that investing in aging research could have. It's simply not being recognized. Although the scientific developments are exciting and cool and coming thick and fast, there's this weird tension between the amount of amazing stuff going on right now and the fact that the field is still dramatically underfunded. Trying to communicate that tension is probably the hardest part of my job.

Each morning after breakfast, Scott Broadbent takes a plastic bottle from the refrigerator in his home in Alameda, Calif., pops the top, and drinks the contents, 2.5 ounces of milky liquid. The bottle might contain ketone ester, a supplement meant to help the body burn fat instead of carbohydrates. Researchers are now testing whether it might also slow the aging process. Or Broadbent might instead be getting a placebo. He is part of a clinical trial at the nearby Buck Institute for Research on Aging to assess the supplement's safety and side effects in older adults.

A retired chemist who used to work for pharmaceutical companies, Broadbent is 70 and in excellent health today, but he worries about the future. He's not necessarily afraid of dying, but he doesn't want to be sick and in pain as he grows older. Some scientists think there's a better way. These researchers - part of a burgeoning field called "geroscience" - aren't seeking immortality. The focus is much more pragmatic: By addressing the root causes of aging, they hope to stave off the disability and diseases that can make old age so miserable. They want to help people feel healthy for longer, compressing the years of illness that often accompany old age into a much shorter time frame.

Though there are no proven therapies for people yet, geroscientists are eyeing several compounds that can slow the aging process, at least in worms, fruit flies, and mice. Some have already been tested in humans, and many more clinical trials are under way. Perhaps the best studied is rapamycin, a compound first discovered in a soil sample collected in 1964 from Rapa Nui, or Easter Island. Today, people who receive organ transplants take the drug to help keep their immune systems from rejecting the foreign tissue. But rapamycin also prolongs life in yeast, flies, and mice. And it's being tested in people in clinical trials. How it counters aging isn't entirely clear. The drug inhibits a protein complex called mechanistic target of rapamycin, mTOR for short, which plays a role in cell growth and protein synthesis. This inhibition appears to have wide-ranging effects, including reducing inflammation, clearing old and damaged cells, and altering cellular metabolism - some of the key processes that researchers think are to blame for the aging process.

Diet is also known to profoundly affect the aging process. Studies have found that the low-carb ketogenic diet, for example, can help mice live longer. But restrictive diets can be hard to follow and have side effects. Broadbent followed the ketogenic diet for a month or so, but his cholesterol levels went dramatically up. Ketone ester, the compound Broadbent might be downing each morning for the Buck Institute's clinical trial, may mimic the longevity benefits of such diets. When the body runs out of glucose to use for energy, the liver creates another source by converting fat into molecules called ketone bodies. These compounds are more than just fuel. They help regulate inflammation and control other cellular processes, many of them involved in the aging process. Drinking ketone esters, which quickly break down, is a way to deliver the ketone bodies without the diet.

Classical evolutionary theories propose tradeoffs between reproduction, damage repair, and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. Here, we use the turquoise killifish (N. furzeri) to genetically arrest germline differentiation at discrete stages, and examine how different 'flavors' of infertility impact life-history.

We first constructed a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. Next, investigating our genetic models revealed that only germline depletion enhanced female damage repair, while arresting germline differentiation did not. Conversely, germline-depleted males were significantly long-lived, indicating that the mere presence of the germline can negatively affect lifespan. Transcriptomic analysis highlighted enrichment of pro-longevity pathways and genes, with functional conservation in germline-depleted C. elegans. Finally, germline depletion extended male healthspan through rejuvenated metabolic functions.

Our results suggest that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative mechanisms to classical evolutionary tradeoffs.

A key pathological factor of Alzheimer's disease (AD), the most prevalent form of age-related dementia in the world, is excessive β-amyloid protein (Aβ) in extracellular aggregation in the brain. And in the peripheral blood, a large amount of Aβ is derived from platelets. So far, the causality between the levels of peripheral blood Aβ and its aggregation in the brain, particularly the role of the peripheral blood Aβ in the pathology of AD, is still unclear. And the relation between the peripheral blood Aβ and tau tangles of brain, another crucial pathologic factor contributing to the pathogenesis of AD, is also ambiguous.

More recently, the anti-Aβ monoclonal antibodies are approved for treatment of AD patients through declining the peripheral blood Aβ mechanism of action to enhance plasma and central nervous system (CNS) Aβ clearance, leading to a decreased Aβ burden in brain and improving cognitive function, which clearly indicates that the levels of the peripheral blood Aβ impacted on the Aβ burden in brain and involved in the pathogenesis of AD. In addition, the role of peripheral innate immune cells in AD remains mostly unknown and controversial.

In the present review, we summarize recent studies on the roles of peripheral blood Aβ and the peripheral innate immune cells in the pathogenesis of AD. In the early stage of disease, the peripheral Aβ is involved in the pathogenesis of AD through activating innate immune cells and promoting them to secretion of inflammatory cytokines and molecules leading to enhancing the blood-brain barrier (BBB) permeability or damage the BBB. In the late stage, the peripheral Aβ may activate the peripheral and central inflammatory processes by affecting the proliferation and differentiation of innate immune cells. The recruitment of the peripheral innate immune cells may lead to increased production of proinflammatory cytokines by microglia, promoting the recruitment of more peripheral innate immune cells to move to the Aβ plaques of brain.

Chronic systemic inflammation and poverty are both linked to an increased mortality risk. The goal of this study was to determine if there is a synergistic effect of the presence of inflammation and poverty on the 15-year risk of all-cause, heart disease and cancer mortality among US adults. We analyzed the nationally representative National Health and Nutrition Examination Survey (NHANES) 1999 to 2002 with linked records to the National Death Index through the date December 31, 2019. Among adults aged 40 and older, 15-year mortality risk associated with inflammation, C-reactive protein (CRP), and poverty was assessed in Cox regressions. All-cause, heart disease, and cancer mortality were the outcomes.

Individuals with elevated CRP at 1.0 mg/dL and poverty were at greater risk of 15-year adjusted, all-cause mortality (hazard ratio [HR] = 2.45) than individuals with low CRP and were above poverty. For individuals with just one at risk characteristic, low inflammation/poverty (HR = 1.58), inflammation/above poverty (HR = 1.59) the mortality risk was essentially the same and substantially lower than the risk for adults with both. Individuals with both elevated inflammation and living in poverty experience a 15-year heart disease mortality risk elevated by 127% and 15-year cancer mortality elevated by 196%.

Pluripotent stem cells can turn into any type of cell in the body. The findings offer a viable path forward for pluripotent stem cell-based therapies to restore tissues that are lost in diseases such as Type 1 diabetes or macular degeneration. "There has been a lot of excitement for decades around the field of pluripotent stem cells and regenerative medicine. What we have learned from the experiences of organ transplantation is that you have to have matched donors, but the person receiving the transplant often still requires lifelong immune suppression, and that means there is increased susceptibility to infections and cancer. We've been trying to figure out what it is that you need to do to those stem cells to keep them from getting rejected, and it looks like we have a possible solution."

To test their hypothesis, researchers used CRISPR-Cas9 technology, "genetic scissors" that allow scientists to make precise mutations within the genome at extremely specific locations. Using human pluripotent stem cells, the team located the specific genes they believed were involved in immune rejection and removed them: β2M, TAP1, CIITA, CD74, MICA, and MICB. Prior research into pluripotent stem cells and immune rejection looked at different parts of the immune system in isolation. The researchers instead opted to test their genetically modified stem cells in a complete and functional immune system.

"Transplantation across species, across the xenogeneic barrier, is difficult and is a very high bar for transplantation. We decided if we could overcome that barrier, then we could start to have confidence that we can overcome what should be a simpler human-to-human barrier, and so that's basically what we did." The research team tested the modified human stem cells by placing them into mice with normal, fully functioning immune systems. The results were promising - the genetically engineered pluripotent stem cells were integrated and persisted without being rejected.

Inflammation is a central component of Alzheimer's disease (AD) pathophysiology, downstream of amyloid beta (Aβ) and tau pathology. Results become heterogeneous when one concentrates on single inflammatory markers, however. These variations may reflect different inflammatory mechanisms in different disease stages. However, a more parsimonious interpretation should take into account that cerebrospinal fluid (CSF) markers are only surrogate measures for an underlying construct, that is, inflammation, which cannot be directly observed in clinical studies.

Mathematically, one can express this epistemological reservation in the framework of structural equation models (SEM). We can construct the inflammatory response in the brain as a latent factor that eludes direct observation but can be assessed by observable proxy markers in the CSF. Confirmatory factor analysis is a readily available tool to form such latent factors. Here, we constructed latent factors for a priori defined inflammatory domains, including synaptic integrity, microglia, complement factors, adhesion, and cytokines/chemokines. We had two goals: First, to determine latent factors of neuroinflammation based on an a priori assignment of single inflammatory markers to certain inflammatory domains. Second, to characterize these neuroinflammation factors in relation to AD pathology markers from CSF and longitudinal rates of cognitive decline.

We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in CSF. We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline.

Aging presents an increasingly significant challenge globally, driven by the growing proportion of individuals aged 60 and older. Currently, there is substantial research interest in pro-longevity interventions that target pivotal signaling pathways, aiming not only to extend lifespan but also to enhance healthspan. One particularly promising approach involves inducing a hormetic response through the utilization of natural compounds defined as hormetins. Various studies have introduced the flavonoid icariin as beneficial for age-related diseases such as cardiovascular and neurodegenerative conditions.

To validate its potential pro-longevity properties, we employed Caenorhabditis elegans as an experimental platform. The accumulated results suggest that icariin extends the lifespan of C. elegans through modulation of the DAF-2, corresponding to the insulin/IGF-1 signaling pathway in humans. Additionally, we identified increased resistance to heat and oxidative stress, modulation of lipid metabolism, improved late-life healthspan, and an extended lifespan upon icariin treatment. Consequently, a model mechanism of action was provided for icariin that involves the modulation of various players within the stress-response network. Collectively, the obtained data reveal that icariin is a potential hormetic agent with geroprotective properties that merits future developments.

Photoaging is a prominent manifestation of skin aging characterized by the appearance of mottled pigmentation, fine lines, and wrinkles. The main molecular mechanisms of photoaging are accumulation of reactive oxygen species, cellular senescence, inflammation, and collagen degradation. Targeting these pathways through novel therapeutics is an intriguing area of study in regenerative medicine.

Exosomes are tiny extracellular vesicles secreted by most cell types, which are filled with proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, DNA), can be released by donor cells to subsequently modulate the function of recipient cells. Exosomes are able to regulate multiple cellular processes due to their important role in cellular communication.

In recent years, exosomes have emerged as a novel therapeutic option for treatment of many diseases. This review aims to summarize the current findings on the roles of exosomes, particularly those derived from stem cells, in the context of skin photoaging. In preclinical studies, stem cell-derived exosomes can restore skin physiological function and regenerate or rejuvenate damaged skin tissue through various mechanisms such as decreased expression of matrix metalloproteinase (MMP), increased collagen and elastin production, and modulation of intracellular signaling pathways as well as, intercellular communication. All these evidences are promising for the therapeutic potential of exosomes in skin photoaging.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Amyloid-β (Aβ), tau, and neuroinflammation are immunotherapy targets focused on by industries for AD intervention. Passive immunotherapy targeting Aβ was launched decades ago and has reached milestone progress with full approval of lecanemab by the FDA very recently. While the development of monoclonal antibody (mAb) drugs targeting tau or immune modulators is at an early stage, several preclinical and clinical studies have shown promising results.

Here, we review characteristics, clinical trial data, and mechanisms of action for mAbs targeting key players in AD pathogenesis, including Aβ, tau, and neuroinflammation modulators. For the anti-Aβ strategy, it should be noted that even the mAbs (lecanemab and donanemab) only showed efficacy in patients with early AD. This may be because other factors, such as tau, have important contributions to neuronal loss in the later stages of AD. In support of this notion, donanemab only showed efficacy in AD patients with low/medium tau pathology.

Therefore, it is important to elucidate the clinical effect of anti-Aβ mAbs on neuronal loss, and it is worth testing the combined immunotherapy strategy targeting both Aβ and tau in patients with moderate symptoms or medium/severe tau pathology in the future. In addition, efficient Aβ-targeted immunotherapy is associated with a high incidence of ARIA and brain atrophy, and the underlying mechanisms need to be clarified. For anti-tau immunotherapy, most of the mAbs recognizing the N-terminal epitopes failed in clinical trials. The industries have now focused on developing mAbs targeting the tau mid-region or phosphorylated tau, which may be able to stop tau seeding and spreading.

To quantify health risks associated with prolonged occupational sitting and to determine whether there is a certain threshold of physical activity that may attenuate it. This prospective cohort study included participants in a health surveillance program in Taiwan who were followed-up between 1996 and 2017. Data on occupational sitting, leisure-time physical activity (LTPA) habits, lifestyle, and metabolic parameters were collected. The all-cause and cardiovascular disease (CVD) mortality associated with 3 occupational sitting volumes (mostly sitting, alternating sitting and nonsitting, and mostly nonsitting) were analyzed applying multivariable Cox regression models to calculate the hazard ratios (HRs) for all participants and by subgroups, including 5 LTPA levels and a personal activity intelligence (PAI)-oriented metric. Deaths occurring within the initial 2 years of follow-up were excluded to prevent reverse causality.

The total cohort included 481,688 participants (mean age 39.3 years). The study recorded 26,257 deaths during a mean follow-up period of 12.85 years. After adjusting for sex, age, education, smoking, drinking, and body mass index, individuals who mostly sat at work had a 16% higher all-cause mortality risk (HR, 1.16) and a 34% increased mortality risk from CVD (HR, 1.34) compared with those who were mostly nonsitting at work. Individuals alternating sitting and nonsitting at work did not experience increased risk of all-cause mortality compared with individuals mostly nonsitting at work (HR, 1.01). For individuals mostly sitting at work and engaging in low (15-29 minutes per day) or no (under 15 minutes per day) LTPA, an increase in LTPA by 15 and 30 minutes per day, respectively, was associated with a reduction in mortality to a level similar to that of inactive individuals who mostly do not sit at work. In addition, individuals with a PAI score exceeding 100 experienced a notable reduction in the elevated mortality risk associated with prolonged occupational sitting.

A new study shows that RNA interference may play a key role in Alzheimer's. For the first time, scientists have identified short strands of toxic RNAs that contribute to brain cell death and DNA damage in Alzheimer's and aged brains. Short strands of protective RNAs are decreased during aging which may allow Alzheimer's to develop.

In addition to long coding RNAs in cells, there are large numbers of short RNAs (sRNAs) which do not code for proteins. They have other critical functions in the cell. One class of such sRNAs suppresses long coding RNAs through a process called RNA interference that results in the silencing of the proteins that the long RNAs code for. Researchers have now identified very short sequences present in some of these sRNAs that when present can kill cells by blocking production of proteins required for cells to survive. The data suggests that these toxic sRNAs are involved in the death of neurons which contributes to the development of Alzheimer's disease.

The toxic sRNAs are normally inhibited by protective sRNAs. One type of sRNA is called microRNAs. While microRNAs play multiple important regulatory roles in cells, they are also the main species of protective sRNAs. They are the equivalent of guards that prevent the toxic sRNAs from entering the cellular machinery that executes RNA interference. But the guards' numbers decrease with aging, thus allowing the toxic sRNAs to damage the cells. Adding back protective microRNAs partially protects brain cells engineered to produce less protective sRNAs from cell death induced by amyloid beta fragments (which trigger Alzheimer's). Enhancing the activity of the protein that increases the amount of protective microRNAs partially inhibits cell death of brain cells induced by amyloid beta fragments and completely blocks DNA damage (also seen in Alzheimer's patients).