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- Mesenchymal Stem Cells Derived via Reprogramming of Old Cells Exhibit a Transcriptomic Signature Closer to that of Younger Cells and Pluripotent Cells
- Towards an Artificial Lymph Node
- Physical Activity, mTOR Signaling, and Alzheimer’s Disease
- Tackling Amyloid-β Oligomers by Interfering in Specific Interactions Necessary to Protein Aggregation
- Dysfunctional and Senescent Immune Cells in Bone Marrow as a Cause of Age-Associated Lineage Skewing of Hematopoietic Stem Cells
- STAT3, FAM3A, and Increased Muscle Stem Cell Activity
- The NYC 2019 Ending Age-Related Disease Conference is Coming Up In July
- A Demonstration of Amyloid-β Clearance via Affibodies in Mice
- A New Approach to Targeting Tau Aggregation in Neurodegenerative Disease
- Light Physical Activity Slows Brain Aging
- Reviewing the Importance of the Blood-Brain Barrier in Brain Aging
- The Influence of p53 on Aging is Far From Fully Understood
- Amyloid-β is not Merely Molecular Waste
- MicroRNAs Assist in Heart Regeneration
- The Debate Continues over Sitting and Its Effects on Mortality
Mesenchymal Stem Cells Derived via Reprogramming of Old Cells Exhibit a Transcriptomic Signature Closer to that of Younger Cells and Pluripotent Cells
In today’s open access paper and publicity materials, researchers report on an assessment of induced mesenchymal stem cells (iMSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were produced via the usual approach of reprogramming from tissue samples taken from old adults. The researchers then compared the gene expression profiles of these iMSCs with similar MSCs taken from fetal and adult tissues. They declare the the profile to be rejuvenated in comparison to that of the adult MSCs, but I think one has to be careful when using that word. We might better call the profile reflective of reprogramming, in that while it has commonalities with the fetal MSCs, it also has has commonalities with the iPSCs, expression of proteins usually not found in adult cells.
The reason for attempting this experiment is that there are concerns regarding the safety and efficacy of MSCs derived from the tissues of old individuals, such as in the case of autologous stem cell therapies. These cells are damaged and in some ways notably dysfunctional, such as in the decline of mitochondrial function. If those cells could be derived instead from a skin sample and then via iPSCs, with many of their age-related defects corrected along the way, acquiring a more beneficial phenotype, then perhaps this would be a better option. The question is always whether or not this is just unsafe in a different direction, such as risk of cancer. A great deal of work is going into answer that question.
Reprogramming somatic cells into iPSCs clearly repairs a range of age-related phenotypes exhibited by cells in old tissues, most notably mitochondrial dysfunction. Moreover, these cells begin to secrete signals that on balance beneficial for regeneration, inflammation, and other aspects of cellular metabolism that become problematic in aging. Most stem cell transplants provided in clinics today work in this way, producing benefits due to the signals issues by the transplanted cells, which soon die rather than integrating into tissues. This signaling and damage repair are the basis for experimental work in inducing pluripotency in the tissues of living animals, and for advances on that work such as the epigenetic not-quite-reprogramming of Turn.bio.
Human iPSC-derived MSCs from aged individuals acquire a rejuvenation signature
The use of primary mesenchymal stem cells (MSCs) is fraught with ageing-related shortfalls such as limited expansion and early senescence. Human induced pluripotent stem cells (iPSCs) -derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these ageing-associated drawbacks. A collaborative study analysed the acquisition of rejuvenation-associated hallmarks in iMSCs. In their study, the team compared cellular features, transcriptomes and secretomes of iMSCs differentiated from embryonic stem cells (ESCs-H1) and iPSCs, emanating from MSCs isolated young and elderly individuals. The generated iMSCs (irrespective of source) met the criteria set out for MSCs and dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and distinct from pluripotent stem cells.
Irrespective of donor age and initial cell type, iMSCs acquired a rejuvenation-associated 50-gene comprising signature which is also expressed in pluripotent stem cells but not in the parental MSCs. Significantly, in terms of regenerative medicine, iMSCs acquired a secretome similar to that of primary MSCs, thus highlighting their ability to act via paracrine signalling. The iMSC concept has enabled circumventing the drawbacks associated with the use of adult MSCs and thus provide a promising tool for use in various clinical settings in the future.
Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature
Primary human bone marrow-derived stem cells (MSCs) contain a sub-population of multipotent stem cells. Due to highly proliferative, immune-modulatory properties, and paracrine orchestration, MSCs offer significant therapeutic potential for an increasing aging demographic. Although the bone marrow can be collected routinely to isolate MSCs, there are several drawbacks associated with the use of MSCs from aged individuals. The expansion possibilities and application potential of primary MSCs are limited, in part, by changes in the differentiation/response potential and function of MSCs isolated from aged donors. However, to date, it remains unclear whether there are any age-related differences in transcriptome and secretome signatures between human fetal MSCs and MSCs from elderly donors.
Recent studies have shown that the shortfalls associated with primary MSCs can be circumvented by reprogramming them to induced pluripotent stem cells (iPSCs). An iPSC-derived cell type that is of prime interest for circumventing shortfalls associated with primary MSCs are MSCs differentiated from iPSCs and ESCs (iMSCs). The similarity of iMSCs to primary MSCs and their regenerative potential in vivo has already been demonstrated. Moreover, the reflection of donor age in iMSCs was shown to be reverted into a younger state and at the same time reflected in iMSCs from patients with early onset aging syndromes. Although the paracrine effects of iMSCs have been indicated, relatively little is known about the potential to rejuvenate the paracrine features of MSCs from elderly patients via iMSC generation.
In view of this, there is a dire need to clarify in more detail whether age-related features inherent to primary MSCs isolated from elderly patients are retained in the corresponding iMSCs at the transcriptional, secretome, and functional level. In this study, we report the age-associated differences between fetal MSC (fMSC) populations and MSCs isolated from elderly donors with respect to their transcriptomes. We successfully reprogrammed fMSCs (55 days post conception) and adult MSC (aMSC; 60-74 years) to iPSCs and, subsequently, generated the corresponding iMSCs. In addition, iMSCs were also derived from ESCs. The iMSCs were similar although not identical to primary MSCs. We unraveled a putative rejuvenation and aging gene expression signature. We show that iMSCs irrespective of donor age and cell type re-acquired a similar secretome to that of their parental MSCs, thus re-enforcing their capabilities of context-dependent paracrine signaling relevant for tissue regeneration.
Towards an Artificial Lymph Node
Artificial structures capable of replicating at least some of the functions of natural organs and tissues may turn out to be quite different in shape, structure, and content when compared to their natural counterparts. This is particularly true for chemical factory tissues, such as the liver, or tissues in which cells migrate and collaborate, such as lymph nodes. In today’s research, scientists demonstrate that a comparatively simple structure can perform some of the same useful functions of a lymph node, at least those related to training and replicating T cells to attack a particular pathogen or cancer cell population.
Natural lymph nodes act as a point of coordination for the immune system, allowing cells to recognize threats and marshal in numbers to fight it. Unfortunately lymph nodes deteriorate and become fibrotic with age, and this degrades the immune response by preventing the necessary coordination between cells. It is a major concern for the many groups attempting to produce rejuvenation of the aged immune system in one way or another. It is interesting to consider that there may be shortcuts towards useful implanted structures in the near future, artificial constructs that are far removed from an actual tissue engineered replacement lymph node, but that nonetheless alleviate a part of this problem. The work here is a very early proof of concept carried out with the goal of replicating T cells more efficiently outside the body, but it could nonetheless be carried forward to potential use in implants.
Scientists Advance Creation of ‘Artificial Lymph Node’ to Fight Cancer, Other Diseases
n the past few years, a wave of discoveries has advanced new techniques to use T-cells – a type of white blood cell – in cancer treatment. To be successful, the cells must be primed, or taught, to spot and react to molecular flags that dot the surfaces of cancer cells. The job of educating T-cells this way typically happens in lymph nodes, small, bean-shaped glands found all over the body that house T-cells. But in patients with cancer and immune system disorders, that learning process is faulty, or doesn’t happen.
CAR-T therapy generally takes about six to eight weeks to culture engineered T-cells in laboratories. To make the engineered T-cells’ environment more biologically realistic, researchers tried using a jelly-like polymer, or hydrogel, as a platform for the T-cells. On the hydrogel, the scientists added two types of signals that stimulate and “teach” T-cells to hone in on foreign targets to destroy. In their experiments, T-cells activated on hydrogels produced 50 percent more molecules called cytokines, a marker of activation, than T-cells kept on plastic culture dishes.
Because hydrogels can be made to order, scientists created and tested a range of hydrogels, from the very soft feel of a single cell to the more rigid quality of a cell-packed lymph node. One of the surprising findings was that T-cells prefer a very soft environment, similar to interactions with individual cells, as opposed to a densely packed tissue. More than 80 percent of T-cells on the soft surface multiplied themselves, compared with none of the T-cells on the most firm type of hydrogel. “As we perfect the hydrogel and replicate the essential feature of the natural environment, including chemical growth factors that attract cancer-fighting T-cells and other signals, we will ultimately be able to design artificial lymph nodes for regenerative immunology-based therapy.”
Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy
T cell therapies require the removal and culture of T cells ex vivo to expand several thousand-fold. However, these cells often lose the phenotype and cytotoxic functionality for mediating effective therapeutic responses. The extracellular matrix (ECM) has been used to preserve and augment cell phenotype; however, it has not been applied to cellular immunotherapies. Here, a hyaluronic acid (HA)-based hydrogel is engineered to present the two stimulatory signals required for T-cell activation – termed an artificial T-cell stimulating matrix (aTM).
It is found that biophysical properties of the aTM – stimulatory ligand density, stiffness, and ECM proteins – potentiate T cell signaling and skew phenotype of both murine and human T cells. Importantly, the combination of the ECM environment and mechanically sensitive TCR signaling from the aTM results in a rapid and robust expansion of rare, antigen-specific CD8+ T cells. Adoptive transfer of these tumor-specific cells significantly suppresses tumor growth and improves animal survival compared with T cells stimulated by traditional methods. Beyond immediate immunotherapeutic applications, demonstrating the environment influences the cellular therapeutic product delineates the importance of the ECM and provides a case study of how to engineer ECM-mimetic materials for therapeutic immune stimulation in the future.
Physical Activity, mTOR Signaling, and Alzheimer’s Disease
Alzheimer’s disease is a condition that sits atop a mound of many contributing causes, layered in chains of cause and effect. Given that chronic inflammation and age-related impairment of the cellular housekeeping mechanisms of autophagy both appear to be significant, somewhere in the mix, it is perhaps to be expected that many of the usual healthy lifestyle choices have some modest impact on the progression of the condition. Exercise and calorie restriction both act to upregulate autophagy and it is thought that this accounts for a sizable fraction of the resulting benefits to health and life span. Unfortunately, the sort of stress response upregulation appears to scale down in impact on life span as species life span increases, though the effects on short term health and metabolism appear quite similar. Mice can live up to 40% longer when on a calorie restricted diet, but that is certainly not true for humans; we gain a few years at most.
Autophagy recycles damaged structures and broken proteins inside the cell. Neurodegenerative conditions such as Alzheimer’s disease involve the presence of toxic molecules, such as those associated with amyloid-β and tau, but even if not directly involved in clearing away disease-associated damage, increased autophagy is generally protective of cell function. Given that this includes everything from neurons to the microglia responsible for clearing away intracellular debris and protein aggregates, we should expect increased autophagy to modestly improve just about every issue in the aging brain. Sadly, doing better than modest improvement is probably not within the scope of what might be achieved via increased rates of autophagy, even when researchers directly influence regulatory genes such as mTOR.
Physical Activity Alleviates Cognitive Dysfunction of Alzheimer’s Disease through Regulating the mTOR Signaling Pathway
Autophagy as an evolutionary-conserved process can maintain normal physiological events or regulate the progression of a series of diseases through sequestering mis-folded/toxic proteins in autophagosomes, thus executing its cytoprotective role. Growing evidence demonstrates that autophagic capacity to degrade harmful proteins in cells declines with increasing age. Moreover, dysfunctional autophagy has also been linked to several aging-related neurodegenerative diseases including Alzheimer’s disease (AD). Previous studies have documented the critical role of autophagy in the pathogenesis of AD, including amyloid-β (Aβ) production or deposition, Aβ precursor protein (APP) metabolism, and neuronal death. Furthermore, insufficient or reduced autophagic activity can lead to the formation of harmful protein aggregates, which results in increased reactive oxygen species (ROS), cell death, and neurodegeneration. As a result, autophagy has a crucial role in the regulation of longevity.
Mammalian target of rapamycin (mTOR) regulates a series of physiological processes. On the one hand, mTOR plays an important role in different cellular processes including cell survival, protein synthesis, mitochondrial biogenesis, proliferation, and cell death. On the other hand, the mTOR signaling pathway can execute an important role in memory reconsolidation and maintaining synaptic plasticity for memory formation, due to its regulatory function for protein synthesis in neurons. Moreover, mTOR also can interact with upstream signal components, such as growth factors, insulin, PI3K/Akt, AMPK, and GSK-3. Currently, although the molecular mechanisms responsible for AD remain unclear, more and more studies have confirmed the involvement of dysregulated mTOR signaling in AD. Activated mTOR signaling is a contributor to the progression of AD and is coordinated with both the pathological and clinical manifestations of AD. Furthermore, there is a close relationship between mTOR signaling and the presence of Aβ plaques, neurofibrillary tangles, and cognitive impairment in clinical presentation. Therefore, the development of mTOR inhibitors may be useful for the prevention and treatment of AD.
It has been reported that regular physical activity can improve brain health and provide cognitive and psychological benefits. Mechanically, regular exercise training is related to the inhibition of oxidative stress and apoptotic signaling, thus effectively executing neuroprotection. Previous studies have demonstrated that treadmill or voluntary wheel running is beneficial for the improvement of behavioral capacity, and can promote the dynamic recycling of mitochondria, thereby improving the health status of mitochondria in brain tissues. Moreover, other studies have demonstrated that regular exercise has a beneficial effect on the structure, metabolism, and function of human and rodent brains. Interestingly, our recent study has also documented that the brain aging of d-gal-induced aging rats can be noticeably attenuated by eight-week swimming training, due to the rescuing of impaired autophagy and abnormal mitochondrial dynamics in the presence of miR-34a mediation. Therefore, physical activity is regarded as an effective approach against AD.
Tackling Amyloid-β Oligomers by Interfering in Specific Interactions Necessary to Protein Aggregation
The present consensus on the the development of Alzheimer’s disease is that it starts with the accumulation of amyloid-β, though there are many competing theories as to why only some people exhibit this problem to a great enough degree to produce pathology. The biochemistry of oligomers supporting amyloid-β causes sufficient disarray in brain metabolism to set the stage for neuroinflammation, malfunction of immune cells in the brain, and aggregation of altered forms of tau protein into neurofibrillary tangles that cause most of the damage and cell death in the later stages of the condition. The failure to improve outcomes via attempts to remove amyloid-β from the brains of Alzheimer’s patients may be a case of too little, too late, but there is still good reason to remove amyloid-β. Doing so early enough and efficiently enough should prevent the later stages of the condition from developing at all.
The most modern approach to drug development, built atop greatly improved capacities in computation and associated modeling of protein structures and interactions, is to find points of intervention through a greater understanding of how proteins interact with one another, in detail, and how those interactions pertain to disease processes. Researchers can then rationally design molecules that (a) interfere at a vulnerable and highly specific point in a desired interaction and (b) due to this specificity are safe enough for clinical use, as they cause only limited disruption elsewhere in the operation of cellular biochemistry. This is the ideal, in any case. The challenge, as ever, is finding a point of intervention that does in fact turn out to be both specific enough and good enough in practice, in patients.
The research noted here today is an example of this approach to development applied to preventing the aggregation of amyloid-β. In principle, sufficient disruption of the process of forming protein aggregates should allow existing systems of clearance to remove excess or damaged protein molecules before they causes issues. In practice, we shall see how it turns out as this work progresses.
Synthetic peptide can inhibit toxicity, aggregation of protein in Alzheimer’s disease
Alzheimer’s is a disease of aggregation. Neurons in the human brain make a protein called amyloid beta. Such proteins on their own, called monomers of amyloid beta, perform important tasks for neurons. But in the brains of people with Alzheimer’s disease, amyloid beta monomers have abandoned their jobs and joined together. First, they form oligomers – small clumps of up to a dozen proteins – then longer strands and finally large deposits called plaques. For years, scientists believed that the plaques triggered the cognitive impairments characteristic of Alzheimer’s disease. But newer research implicates the smaller aggregates of amyloid beta as the toxic elements of this disease.
Now, researchers have developed synthetic peptides that target and inhibit those small, toxic aggregates. Their synthetic peptides – which are designed to fold into a structure known as an alpha sheet – can block amyloid beta aggregation at the early and most toxic stage when oligomers form. The team showed that the synthetic alpha sheet’s blocking activity reduced amyloid beta-triggered toxicity in human neural cells grown in culture, and inhibited amyloid beta oligomers in two laboratory animal models for Alzheimer’s. These findings add evidence to the growing consensus that amyloid beta oligomers – not plaques – are the toxic agents behind Alzheimer’s disease. The results also indicate that synthetic alpha sheets could form the basis of therapeutics to clear toxic oligomers in people.
“This is about targeting a specific structure of amyloid beta formed by the toxic oligomers. What we’ve shown here is that we can design and build synthetic alpha sheets with complementary structures to inhibit aggregation and toxicity of amyloid beta, while leaving the biologically active monomers intact.”
α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease
Alzheimer’s disease (AD) is characterized by the deposition of β-sheet-rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils.
De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.
Dysfunctional and Senescent Immune Cells in Bone Marrow as a Cause of Age-Associated Lineage Skewing of Hematopoietic Stem Cells
The immune system declines with age for a range of reasons. The thymus atrophies, reducing the supply of new T cells; persistent infection by cytomegalovirus causes cells to become uselessly specialized rather than ready to tackle new threats; and the hematopoietic stem cells responsible for generating immune cells become damaged, inactive, and dysfunctional. One of these forms of dysfunction is that hematopoietic stem cells begin to generate too many myeloid cells and too few lymphoid cells, the so-called myeloid skew.
The cause of this skewing in cell production is much debated, but researchers have found that chronic inflammation plays a role. Naturally, nowadays whenever inflammation appears to be an important aspect of any age-related dysfunction, attention turns towards senescent cells. Lingering senescent cells accumulate with age in all tissues, and secrete a potent mix of signals that rouses the immune system into an inflammatory state. It seems likely that they are an important part of the problem when it comes to the myloid skew in the hematopoietic stem cell population.
Why do senescent cells accumulate with age? Cells become senescent in great numbers throughout life, but only later do they linger to a significant degree. Near all are destroyed, either by their own programmed cell death processes, or by the immune system, called into action by the inflammatory signaling of the senescent cells. One reason for a greater number of lingering senescent cells in later life is that the immune system declines and falters in destroying errant cells. Thus, like many issues in aging, the relationship between cellular senescence and immune decline is a circular one; these two processes start off very slowly, but feed one other and accelerate as time passes and damage mounts.
Aged marrow macrophages expand platelet-biased hematopoietic stem cells via Interleukin1B
Dysfunction of the human hematopoietic system with age includes diminished immune response, marrow failure, and clonal selection. Aging is also associated with a general increase in tissue inflammation that remains largely unexplained. The mechanisms driving these characteristics of aged hematopoiesis have, to date, primarily been attributed to intrinsic hematopoietic stem cell (HSC) changes. With age, in both humans and mice, the phenotypic long-term HSC (LT-HSC) pool is expanded and globally LT-HSCs differentiate preferentially towards the myeloid lineage.
Multipotent HSCs with platelet bias were recently identified by a number of investigators describing their increased expression of von Willebrand Factor (vWF) and of the Integrin αIIb (CD41). Recent data demonstrate that aged murine HSCs also have increased cell-surface expression of CD41 and vWF. Notably, human aged HSCs display platelet (or megakaryocytic) bias, suggesting that insights in mechanisms determining murine HSC platelet bias will not only improve our understanding of diseases attributed to the aging hematopoietic system, but also provide novel therapeutic approaches to hematopoietic dysfunction associated with advanced age.
Since the bone marrow microenvironment (BMME) critically regulates HSCs, whether it be considered instructive or enabling distinct HSC fates, unique characteristics of the aged BMME could contribute to HSC changes associated with age. In fact, in the Drosophila gonad, extrinsic signals from the niche contribute to stem cell aging, and mathematical models have suggested that non-cell-autonomous changes could drive this process in mammalian HSCs. While data have suggested that aged endothelial and mesenchymal BMME populations are abnormal and may participate in HSC aging, microenvironmental signals governing the megakaryocytic bias of aged HSCs remain unclear. Thus, we hypothesized that defects in critical BMME populations caused by age could lead to the expansion of platelet-biased HSCs.
We found that macrophages (Mφs) within the aged BMME could impose the megakaryocytic bias characteristic of aging in HSCs. Aged human and murine marrow Mφs had distinct transcriptional profiles compared to young Mφs, including an increased inflammatory activation signature. We identified increased interleukin 1B (IL1B) mRNA in aged marrow Mφs and elevated caspase 1 activity in Mφs and neutrophils from aged bone marrow. Moreover, IL1B signaling was necessary and sufficient to induce HSC bias and drive young HSPCs to adopt an aged phenotype.
While investigating the cause of this increase, we made the novel observation that aged marrow Mφs had a defect in efferocytosis – their ability to clear apoptotic cells. Clearance of apoptotic cells is a critical function of Mφs that prevents necrosis of dead cells and associated local inflammation and also triggers anti-inflammatory responses in phagocytes. In young mice, removal of phagocytic cells or genetic loss of the efferocytic receptor Axl increased HSCs with megakaryocytic bias, suggesting that the efferocytic defect in aged marrow Mφs leads to the increase in IL1B activation and signaling. Together these data define a novel mechanism within the aged BMME that enables a specific HSC fate.
STAT3, FAM3A, and Increased Muscle Stem Cell Activity
Expression of the STAT3 gene influences a number of vital cellular processes, such as mitochondrial activity, cellular differentiation, and cellular proliferation. Researchers have investigated its activity in the context of spurring greater regenerative activity in heart muscles, for example. Arguably this is a good example of a regulatory gene that is involved in too many processes to make it a good target for therapeutics, however. More specific, lower-level mechanisms for specific desired goals would be helpful. That requires slow and costly investigative work, however, picking apart the relationships between proteins and their roles.
Researchers have uncovered a molecular signaling pathway involving Stat3 and Fam3a proteins that regulates how muscle stem cells decide whether to self-renew or differentiate – an insight that could lead to muscle-boosting therapeutics for muscular dystrophies or age-related muscle decline. “Muscle stem cells can ‘burn out’ trying to regenerate tissue during the natural aging process or due to chronic muscle disease. We believe we have found promising drug targets that direct muscle stem cells to ‘make the right decision’ and stimulate muscle repair, potentially helping muscle tissue regeneration and maintaining tissue function in chronic conditions such as muscular dystrophy and aging.”
Muscle wasting occurs as part of the natural aging process, called sarcopenia, or due to genetic diseases such as muscular dystrophy. Sarcopenia affects nearly 10 percent of adults over the age of 50 and nearly half of individuals in their 80s. Muscle stem cells select between two fates over a person’s lifetime: Either differentiate to become adult muscle cells or self-renew to replenish the stem cell population. Accumulating evidence shows that mitochondrial respiration is a key switch that drives muscle stem cells to differentiate, an energy-intensive process, instead of self-renew.
In the study, the scientists used mouse models to demonstrate that Stat3 promotes mitochondrial respiration. Because Stat3 regulates many cellular processes, the scientists combed through genes expressed during muscle growth to find additional proteins regulated by Stat3 that might serve as more specific targets. These efforts uncovered the protein Fam3a. Further work conducted, including generating a mouse model and cell lines that lack Fam3a, demonstrated that the protein is required for muscle stem cell differentiation and muscle growth. The researchers also showed that Fam3a is secreted by muscle cells during muscle repair, and treatment with the protein restored mitochondrial respiration and stem cell differentiation in muscle stem cells that lacked Stat3 – all demonstrating the integral role of Fam3a in determining muscle stem cells’ fate.
The NYC 2019 Ending Age-Related Disease Conference is Coming Up In July
It isn’t long now until the Life Extension Advocacy Foundation will be hosting their second Ending Age-Related Diseases conference in New York City. The event takes place on July 11th and 12th this year, and features a mix of noted researchers, investors, and entrepreneurs involved in the present development of means to treat aging as a medical condition. Last year’s conference was a great event for networking with new members of our growing longevity science and advocacy community, and video of the presentations can be found online.
Aging research is on the cusp of some major breakthroughs in the battle against age-related diseases, and we invite you to join us for an action-packed event filled with exciting talks and discussion panels featuring some of the leaders of aging research and the biotech business. We are still announcing more speakers for this exciting event and think that today is a great time to update everyone about what has been happening. We are delighted that Dr. Maria Blasco will be speaking at the conference this year. Dr. Blasco is a true pioneer in aging research, and her work with cancer and telomeres is well known.
Dr. João Pedro de Magalhães from Liverpool University has also just confirmed that he is going to be speaking at the event this year. Dr. Magalhães believes that the complexity and multi-dimensional nature of aging require that this biological problem be tackled using a combination of disciplines and approaches. He and his team have been conducting studies of the genetics, physiology, and cell biology of long-lived animals. He is perhaps best known for his genetic studies on long-lived species, such as the bowhead whale and the naked mole rat.
We will also be joined by Dr. Michael Lustgarten from Tufts University. Dr. Lustgarten is no stranger to us, as he has appeared in an episode of the Journal Club, a special microbiome webinar, and an interview with us. Dr. Lustgarten is a researcher at the Nutrition, Exercise Physiology, and Sarcopenia Laboratory (NEPS) at the Human Nutrition Research Center on Aging at Tufts. His research is focused on how the gut microbiome and serum metabolome affect muscle mass and function in older people. Dr. Lustgarten is an expert on the gut microbiome, exercise, biomarkers, and nutrition.
A Demonstration of Amyloid-β Clearance via Affibodies in Mice
While clearing out amyloid-β from the brain has so far proven to be a matter of too little, too late in late stage Alzheimer’s disease patients, there is still a strong basis of evidence for the merits of removing amyloid-β. It is reasonable to say that it causes meaningful pathology; if people did not accumulate amyloid-β deposits, then there would be no consequent disarray in the function of neurons and immune cells in the brain. This particular foundation of the development of dementia would be removed. Even if the mechanisms of the later stages of Alzheimer’s, the chronic inflammation and tau protein aggregation, for example, were blocked, then amyloid-β accumulation would still cause at least mild cognitive impairment on its own. Thus despite the continued failure of clinical trials, even those in which amyloid-β was in fact cleared to a fair degree from the brains of Alzheimer’s patients, we should still be encouraged by new approaches and other signs of progress in this area of the field.
Present therapies for Alzheimer’s disease (AD) have either no or minimal disease-modifying effect, and thus, there is an urgent need for new effective treatments. Numerous therapeutic strategies are under investigation to delay the onset or slow progression of the disease. Active and passive immunotherapeutic approaches have been suggested to improve clinical progression and cognitive impairment through different mechanisms: (i) inhibition of amyloid-β (Aβ) production; (ii) interference with the formation of toxic aggregation intermediates; and (iii) accelerated clearance of Aβ from the central nervous system into the periphery.
Several anti-Aβ antibodies have demonstrated effective clearance of Aβ together with cognitive improvements in transgenic animal models and consequently progressed to clinical trials. However, translation to safe and efficacious therapies for humans has been challenging as AD clinical trials have failed to show sufficient clinical benefits. Recently, the monoclonal antibody (mAb) Solanezumab, that binds monomeric Aβ, was extensively evaluated in a phase III prevention trial in patients with mild AD. The study was however terminated due to failure in showing cognitive improvements.
It has been proposed that challenges related to the failure in showing overall clinical improvement or clear disease-modifying results of these mAbs could be addressed to some of the inherent properties of antibodies. Thus, new approaches based on engineered antibody domains or alternative scaffold-proteins that generally lack immunoglobulin-related effector functions are now investigated and moving into clinical development, as they might provide safer and more effective treatments. Antibody derivatives and non-immunoglobulin affinity proteins are in general smaller than full-length antibodies. Their smaller size could potentially result in a different in vivo biodistribution profile as well as simplified administration routes, which could be important in the treatment of e.g., AD.
Affibody molecules represent a class of promising alternative scaffold proteins that have been investigated for various applications. We have previously reported on the generation of an affibody molecule (denoted ZAb3) that binds to monomeric Aβ. This Aβ-sequestering affibody molecule has demonstrated efficient inhibition of formation of Aβ aggregates in an in vivo Drosophila AD model, and abolished the neurotoxic effects as well as restored the life span of the flies. The affibody molecule was further engineered into a truncated genetic dimer, ZSYM73-ABD.
Encouraged by these positive results, we here investigate the efficacy of ZSYM73-ABD as a therapeutic candidate to prevent the development of AD-related pathology in transgenic AD mice. The animals received three weekly injections of 100 μg therapeutic protein or negative control protein during 13 weeks, starting at the expected onset of pathology development. Extensive behavioral assessment together with histological evaluation demonstrated a significantly lower amyloid burden in both cortex and hippocampus, as well as rescued cognitive functions of the ZSYM73-ABD treated mice relative to controls.
A New Approach to Targeting Tau Aggregation in Neurodegenerative Disease
Researchers here report on discovering that an existing farnesyltransferase inhibitor drug reverses the accumulation of altered tau protein aggregates in a mouse model. The death and dysfunction of nerve cells in the neurodegenerative conditions known as tauopathies is driven by the formation of neurofibrillary tangles, made of tau protein. That in turn has deeper causes, such as the chronic inflammation produced by senescent cells and disruption of immune cell activity in the central nervous system, one of which is no doubt being adjusted in some way by the action of the drug in this case. As in all such quite indirect mechanisms, there is the question as to whether results in mice will translate to humans in any useful way. In the case of an existing drug, there is at least a shorter path to an answer.
Tau, a protein found primarily in neurons, is typically a somewhat innocuous, very soluble protein that stabilizes microtubules in the axon. However, when soluble, stable tau misfolds the resulting protein becomes insoluble and tangled, gumming up the works inside the neuron as a neurofibrillary tangle. In one of several neurodegenerative diseases caused by tau, frontotemporal dementia, the frontal and temporal lobes of the brain are impaired, resulting in problems with emotion, behavior and decision-making.
By taking skin cell samples from a few individuals who harbor tau mutations and converting them in vitro into stem cells, and then into neurons, researchers found that three genes were consistently disregulated in those with tau mutations, one of which was of particular interest: RASD2 – a gene expressed primarily in the brain that belongs in a family that catalyzes energy-producing molecules (GTPases) and which has been studied extensively. A GTPase called Rhes is encoded by the gene RASD2. Like its cousins in the Ras superfamily, Rhes is a signaling protein that does its work on the cell surface, where it is attached to the inner membrane by a small carbon chain – a farnesyl group – through a process called farnesylation.
This attachment has been the target of a couple decades of cancer research under the assumption that if the Ras protein connection to the cell membrane could be interrupted, so would the signals that cause unregulated growth of tumor cells and other cancer behaviors. The drugs in this category, called farnesyltransferase inhibitors, have been tested in humans. But, they did not work in cancer.
In mice models with frontotemporal dementia, however, it seems they do. And the results are dramatic. Using the drug Lonafarnib, the researchers treated mice who at 10 weeks were erratic – running around in circles or completely apathetic – and by 20 weeks they were sniffing around their cage or nest building and doing other normal mouse behaviors. Scans revealed the arrest of brain tissue deterioration and inflammation. Most dramatic: The once-insoluble neurofibrillary tangles were greatly reduced, and in some areas including the hippocampus – the memory part of the brain – were nearly completely gone. To prove the drug was targeting the farnsylated Rhes protein, the scientists introduced into the brains of other mouse models an inhibitory RNA gene that specifically suppresses the production of Rhes. And the results completely replicated the effects of the drug.
Light Physical Activity Slows Brain Aging
In recent years, with the enthusiastic adoption of accelerometers by the designers of epidemiological studies, it has become clear that even quite modest levels of physical activity correlate strongly with improved health and a slower pace of age-related degeneration. In most human data there is no way to establish which of these is cause and which of these is consequence, but animal studies are quite definitive on the point that exercise produces improvements in health, even if it doesn’t appear to extend life span. Physical activity, like all interventions, has a dose-response curve, and there is a sizable difference between being sedentary and being even modestly active. It is still a better idea to be more than just modestly active, of course; research suggests that the recommended levels of exercise, 150 minutes per week, may well be too low.
Considerable evidence suggests that engaging in regular physical activity (PA) may prevent cognitive decline and dementia. Active individuals have lower metabolic and vascular risk factors, and these risk factors may explain these individuals’ propensity for healthy brain aging. Even short-term exercise interventions have been shown to prevent hippocampal atrophy in older adults11 and may also improve brain connectivity. Furthermore, cross-sectional epidemiologic studies have established an association of physical inactivity with brain aging. However, further work is needed to pinpoint the optimal dosage of PA needed to promote healthy brain aging.
A growing body of literature has established light-intensity PA as an important factor for improving health outcomes, but in our review of the literature, light-intensity PA has not often been considered separately from total PA for its association with brain structure. Previous studies have identified positive associations of self-reported PA with brain volume, but accelerometry studies often have smaller sample sizes and have focused on examining the association of total PA with brain volume. However, PA variables are associated with one another, so in our analyses, we went a step further and modeled them together to determine what type of PA intensity (low or high) is driving the association of PA with brain volume.
The simplification of PA as a predictor variable has potentially masked more nuanced associations of components of PA with brain health. Compared with previous research, our study provides multiple PA levels and intensities and uses accelerometry-determined intensity thresholds (ie, light-intensity PA and moderate to vigorous PA) in the same statistical models to provide a more sensitive measure of PA doses and examine what type of PA is driving the associations we observe.
The study sample of 2354 participants had a mean age of 53 years, 1276 were women, and 1099 met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging. Among individuals not meeting the PA guidelines, each hour of light-intensity PA and achieving 7500 steps or more per day were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume.
Reviewing the Importance of the Blood-Brain Barrier in Brain Aging
The blood-brain barrier is a specialized layer of cells that wrap blood vessels passing through the central nervous system, ensuring that only certain molecules can pass in either direction. Thus the biochemistry of the central nervous system is kept distinct from that of the rest of the body. This separation is necessary for correct function, as illustrated by the point that the blood-brain barrier begins to break down with advancing age. This produces damage and dysfunction in the brain, as unwanted cells and molecules leak through the faulty blood-brain barrier. As noted here, however, the relative scope and size of this contribution to neurodegeneration, in comparison to other contributing factors, is far from fully determined.
Changes in the immune system have long been recognized to occur with aging, and it is now appreciated that neuroinflammation likely contributes to age-associated neurological diseases. However, it is less well understood how specific changes in the immune system with aging may affect central nervous system (CNS) functions and contribute to neurological disease. We posit that brain barriers, especially the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are important interfaces between CNS and peripheral tissues that are affected by age-associated changes in the immune system. The BBB/BCSFB may, in turn, affect homeostatic functions of the CNS, and/or exhibit more detrimental responses to pathological stimuli.
One of the most-studied (and yet, poorly understood) aspects of BBB dysfunction is disruption, which is typically defined by the apparent leakage of normally BBB impenetrant molecules. Recent imaging results argue that BBB disruption does occur in healthy aging, and is worse in individuals with mild cognitive impairment, which is considered a prodrome of Alzheimer’s disease (AD). One common approach to proxy BBB disruption in living humans is to measure the ratio of abundant, BBB-impermeant proteins such as albumin or immunoglobulin G (IgG) in cerebrospinal fluid (CSF) versus serum. However, these measures may be confounded by other known CNS deficits with aging, such as altered production and reabsorption of CSF, and inflammatory changes in the serum and CSF levels of these proteins. Further, there may be leakage of the BCSFB and altered protein synthesis at this site with age. Recent studies have implemented advanced imaging technologies that can visualize leakage of intravenously injected tracers via dynamic contrast MRI, and these have indicated that vascular BBB disruption does occur in the aging human brain, albeit at low levels.
In healthy aged mice, leakage of IgG into the parenchymal space of the cerebral cortex and hippocampus occurs when compared with young mice, suggesting that there is BBB disruption in this model. Increased IgG leakage in aged mice was associated with astrogliosis, endoplasmic reticulum (ER) stress, and increased endothelial cell levels of TNF-α; the latter measure significantly correlated with circulating levels of IL-6. In the same study, a significant reduction in occludin expression per brain endothelial cell was also observed in aged mice. Other studies have corroborated findings of BBB disruption in aging mice. Molecular mechanisms of BBB disruption in aging have been identified, and include reduced expression of sirtuin-1, a de-acetylase enzyme which has been implicated in the regulation of lifespan, senescence, and inflammatory responses to environmental stress.
BBB disruption in the context of aging or disease could result in disease exacerbation through leakage of potentially harmful proteins into the brain. However, it is not entirely clear that BBB disruption under any circumstance will always lead to brain damage. For example, certain therapeutic strategies for delivery of chemotherapeutics to the brain have relied on transiently disrupting the BBB, and are generally well-tolerated when brain cancers are the target. Recent work has also indicated that repeated transient BBB disruption in humans with AD using focused ultrasound did not cause any serious clinical or radiological adverse events. In contrast, healthy rodents with no prior brain abnormalities showed symptoms of reactive gliosis and neurodegeneration when transiently perfused with mannitol to cause widespread disruption of the BBB, and also had increased deposition of harmful serum proteins like fibrinogen in the CNS. The apparent paradox in efforts to disrupt the BBB as a therapeutic strategy versus BBB disruption having known adverse consequences on the CNS and associations with many CNS diseases highlights the complexities of BEC barrier functions that are likely nuanced and context-specific. Why BBB disruption in and of itself is apparently innocuous under some conditions, but clearly detrimental in others remains to be understood in greater molecular detail.
The Influence of p53 on Aging is Far From Fully Understood
The p53 protein sits at the intersection of aging and cancer. Too much p53 activity and cell is activity is shut down, cells are made senescent more aggressively, and this leads to accelerated aging. Too little p53 activity, and precancerous cells might survive to form an ultimately fatal tumor. This is a considerable oversimplification of a very complex set of systems, however. There are plenty of exceptions to the above rule, including examples of conditional upregulation of p53 in mice that both extends life and reduces cancer incidence. The open access paper here discusses some of the complexities and contractions in what is known of the role of p53 – a gene that is well studied, but not yet comprehensively understood.
To accelerate aging, p53 induces apoptosis or cell cycle arrest as a prerequisite to cellular senescence; both can impair the mobilization of stem and progenitor cell populations. To suppress aging, p53 inhibits unregulated proliferation pathways that could lead to cellular senescence and a senescence-associated secretory phenotype (SASP), which creates a pro-inflammatory and degenerative tissue milieu. A review of mouse models supports both possibilities, highlighting the complexity of the p53 influence over organismal aging. These models were originally designed to study cancer but some appear to impact aging and longevity as well. They range from complete p53 null mutations to truncations or point mutations that alter activity. A comparison of these models reveals the complex influence p53 has over organismal aging – which can be independent or a consequence of its tumor suppressor role.
The initial mouse models were simple knockouts that produced no p53 protein. Most p53-/- embryos developed into apparently healthy adults, almost all of which succumb to cancer in about half a year. Heterozygous (p53+/-) mice develop cancer at a later age. Since simple p53-deletion increases cancer, simple overexpression should reduce cancer. Indeed, mice harboring an extra p53 gene contained within a BAC (bacterial artificial chromosome) had a lower incidence of cancer with no obvious effect on aging. Furthermore, increased gene dosage of p53 together with Arf lowered the cancer incidence and improved overall survival. ARF elevates p53 levels by inhibiting MDM2. Similarly, mice with a hypomorphic MDM2 allele, which increased p53 levels, showed a reduced cancer incidence without deleterious side effects. Thus, enhanced p53-mediated cancer suppression was not toxic to adult mice. It is possible that the pro-aging side effects of p53 are manifest only when p53 overwhelms the many regulatory mechanisms that modulate its activity.
The p53-null and p53-elevated mouse models support a simple notion of function; that is, p53 suppresses cancer without toxic side effects. However, other p53-altered mouse models confound this notion. p53 levels influenced aging in mice defective for BRCA1. BRCA1 repairs DNA double strand breaks (DSBs) created during DNA replication as a part of the homologous recombination repair pathway. Deleting one copy of p53 rescued brca1-/- mice from embryonic lethality but these mice displayed an early aging phenotype. Moreover, decreased capacity to repair DSBs caused p53-dependent early cellular senescence in cells and early organismal aging. Another genetic alteration that implicates p53 in aging is REGγ. REGγ-deficient mice display early aging. Elevated p53 might contribute to this phenotype because REGγ is a proteasome activator that regulates p53. Finally, skin-specific MDM2 deficiency resulted in p53-induced senescence in epidermal stem cells and precocious skin aging. These examples are interesting contrasts to the MDM2 hypomorphic allele described above, which reduced cancer without side effects, and suggests that different aspects of p53 regulation, coupled with genetic and environmental variances, can drive distinct biological outcomes.
Further complicating the picture, there are multiple p53 isoforms and family members (p63 and p73) generated from variant promoter usage, alternative splicing, and alternative translation initiation. How these isoforms differ functionally is not fully understood. There is evidence that some of these isoforms could influence aging. For example, expression of the N-terminally truncated p53 isoform in mice lowered cancer risk at the expense of early aging. These mice showed poor tissue regeneration, implicating a defect in stem and progenitor cells. Supporting this possibility, old p53+/- mice exhibited increased levels of hematopoietic stem and progenitor cells, but not if N-terminally truncated p53 was present. The truncated p53 likely forms a tetramer with full-length p53 to improve stability and nuclear localization. Another isoform stabilized p53 in the presence of MDM2. Thus, p53 isoforms have the potential to influence p53 function in a manner that affects aging.
Amyloid-β is not Merely Molecular Waste
Alzheimer’s disease begins with the accumulation of amyloid-β in the brain, but this doesn’t mean that amyloid-β is purely molecular waste. Yes, it is harmful given the presence of too much of it in the central nervous system, but that is true of most of our biochemistry. There is good evidence for amyloid-β to act as an antimicrobial system, for example, which is the basis for considering persistent infection as a potential contributing cause of Alzheimer’s disease, in which infectious agents drive the generation of ever increasing amounts of amyloid-β. Even setting aside that and other evidence, however, it is quite possible to argue that amyloid-β must have some important function, based on evolutionary theory and the fact that the molecule exists at all.
The argument is frequently made that the amyloid-β protein (Aβ) persists in the human genome because Alzheimer’s disease (AD) primarily afflicts individuals over reproductive age and, therefore, there is low selective pressure for the peptide’s elimination or modification. This argument is an important premise for AD amyloidosis models and therapeutic strategies that characterize Aβ as a functionless and intrinsically pathological protein. Here, we review whether evolutionary theory and data on the genetics and biology of Aβ are consistent with low selective pressure for the peptide’s expression in senescence.
Aβ is an ancient neuropeptide expressed across vertebrates. Consistent with unusually high evolutionary selection constraint, the human Aβ sequence is shared by a majority of vertebrate species and has been conserved across at least 400 million years. Unlike humans, the overwhelming majority of vertebrate species do not cease reproduction in senescence and selection pressure is maintained into old age. Hence, low selective pressure in senescence does not explain the persistence of Aβ across the vertebrate genome.
The Grandmother hypothesis (GMH) is the prevailing model explaining the unusual extended postfertile period of humans. In the GMH, high risk associated with birthing in old age has lead to early cessation of reproduction and a shift to intergenerational care of descendants. The rechanneling of resources to grandchildren by postreproductive individuals increases reproductive success of descendants. In the GMH model, selection pressure does not end following menopause. Thus, evolutionary models and phylogenetic data are not consistent with the absence of reproductive selection pressure for Aβ among aged vertebrates, including humans.
Our analysis suggests an alternative evolutionary model for the persistence of Aβ in the vertebrate genome. Aβ has recently been identified as an antimicrobial effector molecule of innate immunity. High conservation across the Chordata phylum is consistent with strong positive selection pressure driving human Aβ’s remarkable evolutionary longevity. Ancient origins and widespread conservation suggest the human Aβ sequence is highly optimized for its immune role.
MicroRNAs Assist in Heart Regeneration
Many researchers are exploring the therapeutic utility of microRNAs involved in fundamental cellular processes such as replication. These molecules act to regulate the processes of gene expression, determining how much of specific proteins are produced from their genetic blueprints, and when. Protein amounts are the switches and dials of cellular operation, and delivering microRNAs into cells is one possible way to steer cells into useful behavior – through the sheer complexity of the cell makes identifying the right tools to use quite difficult, and any given microRNA may produce quite sweeping changes, only few of which are helpful in any given context. Nonetheless, as illustrated here, there are some possible paths forward towards near future applications of microRNA delivery in regenerative medicine.
Once the heart is fully formed, the cells that make up heart muscle, known as cardiomyocytes, have very limited ability to reproduce themselves. After a heart attack, cardiomyocytes die off; unable to make new ones, the heart instead forms scar tissue. Over time, this can set people up for heart failure. New work advances the possibility of reviving the heart’s regenerative capacities using microRNAs – small molecules that regulate gene function and are abundant in developing hearts. Researchers had earlier identified a family of microRNAs called miR-17-92 that regulates proliferation of cardiomyocytes. In the new work, they show two family members, miR-19a and miR-19b, to be particularly potent and potentially good candidates for treating heart attack.
Researchers tested the microRNAs delivered two different ways. One method gave them to mice directly, coated with lipids to help them slip inside cells. The other method put the microRNAs into a gene therapy vector designed to target the heart. Injected into mice after a heart attack – either directly into the heart or systemically – miR-19a/b provided both immediate and long-term protection. In the early phase, the first 10 days after heart attack, the microRNAs reduced the acute cell death and suppressed the inflammatory immune response that exacerbates cardiac damage. Tests showed that these microRNAs inhibited multiple genes involved in these processes. Longer-term, the treated hearts had more healthy tissue, less dead or scarred tissue and improved contractility, as evidenced by increased left-ventricular fractional shortening on echocardiography. Dilated cardiomyopathy – a stretching and thinning of the heart muscle that ultimately weakens the heart – was also reduced.
The Debate Continues over Sitting and Its Effects on Mortality
Do periods of sedentary behavior, in particular sitting, increase the risk of mortality and age-related disease regardless of whether or not there are periods surrounding exercise? The epidemiological research community can take decades and dozens of studies to chew over questions like this. Most recently, evidence was presented to suggest that sitting for longer periods of time is an independent risk factor for mortality even for those who exercise. The study here presents evidence for a more nuanced conclusion, that exercise does compensate for periods of time spent sitting.
This sort of contradictory data is very much par for the course in this area of study: ignore any single set of results, and look for consensus across as many studies as possible. Meanwhile consider whether or not the arrow of causation might point from health and mortality risk to behavior such as sitting and activity; are less active people exhibiting higher mortality because unhealthy people tend to be less active, for all the obvious reasons, for example?
For less active adults, the amount of time spent sitting may be associated with an increased risk of death; however, increasing physical activity to recommended levels may eliminate this association in some. Recent studies have determined that high levels of sedentary behavior are associated with adverse health outcomes. However, the link between sedentary behavior, mortality, and heart disease are not always well understood.
In this study, researchers aimed to determine the association between sedentary behavior and physical activity on mortality and to estimate the effects of replacing sitting with standing, physical activity and sleep. Participants included 149,077 Australian men and women aged 45 years and older who were asked to complete a questionnaire that determined how many hours per day an individual spent sitting, standing and sleeping. They also were questioned about the total time spent walking or participating in moderate or vigorous physical activity.
After a median follow up time of 8.9 years for all-cause mortality and 7.4 years for cardiovascular disease mortality, higher sitting times (more than six hours) were associated with higher all-cause and cardiovascular disease mortality risks, but mostly in those did not meet physical activity recommendations. Meeting even the lowest requirements for physical activity eliminated the association with all-cause mortality risk, with the exception of those who sat the most (more than 8 hours a day). Compared to those who were highly active and sat for less than four hours per day, the risk remained substantially elevated even among physically inactive participants who sat for 4 hours per day only.
While replacing sitting with standing was associated with risk reduction in low sitters, replacing sitting with physical activity was more consistently associated with risk reduction in high sitters. The researchers found that moderate physical activity only reduced cardiovascular disease death risk among high sitters. The largest replacement effects were seen for vigorous physical activity, but this level of activity may not be possible for all adults.
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