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- Have Specific Genetic Examples of Antagonistic Pleiotropy Been Identified in Humans?
- The Engineering of Kidney Organoids Proceeds Apace
- Signs of Cellular Senescence in Aged Bone Marrow, Contributing to Impaired Generation of Immune Cells
- SGLT-2 Inhibitors as Calorie Restriction Mimetics
- Ccna2 as a Novel Regulator of Cellular Senescence
- More of Just one Component Part of a Proteasome Extends Life in Worms and Flies
- Aging and Oxidative Signaling in Muscle Tissue
- More on Poor Sleep and Levels of Tau in the Brain
- Correlating CMV Infection and Markers of Inflammation in Older Individuals
- Fewer Calories, Better Cell Performance
- Fasting Mimicking Diet as a Treatment for Inflammatory Bowel Disease
- Greater Fitness in Old Age Correlates with Greater Ten Year Survival Rates
- A Review of DNA Methylation Based Epigenetic Clocks as a Measure of Aging
- Burden of Age-Related Disease Varies Broadly Between Regions of the World
- Proposing the IMM-AGE Metric to Measure the Aging of the Immune System
Have Specific Genetic Examples of Antagonistic Pleiotropy Been Identified in Humans?
Pleiotropy occurs when a single gene affects more than one distinct and seemingly unrelated trait. Antagonistic pleiotropy occurs when one of those traits is harmful. It is widely considered to be an important foundation for the evolution of aging, in that natural selection operates strongly during early life, a period characterized by tooth and claw battles for survival and reproductive success. Evolution will select for genes, mechanisms, and biological systems that operate well early and run down later, or otherwise cause harm in later life. The adaptive immune system is an example of the type, a system that works very well right out of the gate in youth, but cannot possibly function indefinitely. It devotes resources to all pathogens encountered, and eventually simply runs out of capacity. The decline of the immune system is much more complex than that simple sketch, of course, and has numerous distinct causes, but the example serves.
In the broader sense, why doesn't the body repair itself indefinitely? The antagonistic pleiotropy hypothesis suggests that the fierce selection pressure in early life will strip away anything that isn't absolutely vital to immediate survival and reproductive success. Long-term investment in repair and maintenance simply cannot survive this evolutionary arms race, in which even a tiny loss of advantage may well lead to extinction of the lineage. This might lead us to wonder how the lowly hydra manages to be functionally immortal, actually ageless - but it is only one among countless species that all undergo degenerative aging. Perhaps we are seeing the hydra shortly before its inevitable extinction at the hands of a slightly more efficient rival.
The two commentaries here follow on from a recent paper that discussed antagonistic pleiotropy and the evidence for it. Everyone involved in the exchange appears to support the antagonistic pleiotropy hypothesis; the debate is over whether or not specific named genes in humans are clearly pleiotropic in this way, and whether the evidence in support of that position is robust. As the authors of the original paper note, the challenge inherent in human data is that it produces correlations rather than the definitive causation that can be obtained from a well-designed animal study.
Byars and Voskarides: Genes that improved fitness also cost modern humans, evidence for genes with antagonistic effects on longevity and disease
Austad and Hoffmann reviewed the current state-of-the-art on what support there is for the theory of antagonistic pleiotropy and what implications this has for modern medicine regarding improving human health and longevity. Although the authors focus on examples in both wild populations and laboratory conditions, the review states that there are no compelling examples in humans where the underlying genes or alleles that carry this tradeoff have been identified. This fails to acknowledge recent studies, mostly published the last two years, where excellent progress has been made in identifying such genes and below, we describe several examples.
Two studies in 2017 uncovered evidence for antagonistic pleiotropy in genes related to coronary heart disease (CAD) and fitness, and diseases related to ageing. The first found that CAD genes in humans are significantly enriched for fitness (increased lifetime reproductive success) relative to the rest of the genome, with evidence that the direction of their effects on CAD and fitness are antagonistic. This study provides a possible reason why genes carrying health risks have persisted in human populations. The second found evidence for multiple variants in genes related to ageing that exhibited antagonistic pleiotropic effects. They found higher risk allele frequencies with large effect sizes for late-onset diseases (relative to early-onset diseases) and an excess of variants with antagonistic effects expressed through early and late life diseases.
There also exists other recent tangible evidence of antagonistic pleiotropy in specific human genes. The SPATA31 gene has been found under strong positive genomic selection. Long-lived individuals carry fewer SPATA31 copy numbers. On the other hand, its overexpression in fibroblast cells leads to premature senescence, this being the case in people having multiple copies of the gene. During human evolution, more copies of this gene have likely been favored since this protein is important in sensing and repairing UV-induced DNA damage. Unfortunately, the cost is cell senescence and premature aging.
Austad and Hoffmann: Response to genes that improved fitness also cost modern humans: evidence for genes with antagonistic effects on longevity and disease
Byars and Voskarides, responding to our review of empirical support for the antagonistic pleiotropy theory of the evolution of aging, feel that we have 'failed to acknowledge' recent human studies supporting the theory. Indeed, we mentioned no human studies because we had intended our review to present only the strongest evidence supporting the theory which has been done almost entirely in laboratory model organisms. For this reason, while we mentioned a few studies from natural populations, we emphasized how such nonexperimental studies could be consistent with the antagonistic pleiotropy mechanisms, but could not be cleanly attributed to it. Experimental studies establish cause-and-effect in a way that correlational studies cannot.
It is an unfortunate truth about research on humans that because experimental studies are often impossible, results are almost inevitably correlational, which in our view makes virtually any single study highly suggestive at best, but never compelling. To illustrate why, we consider one of the studies adduced by Byars and Voskarides, although we could have chosen any of the others. That study identifies numerous human alleles pre-disposing individuals to coronary artery disease (CAD) but also conferring reproductive advantages early in life. This is a very nice study given the limitations of human research. The best that could be done with available data was done. Note, however, that one of the first lessons of statistical reasoning is that correlation does not equal causation and, yes, genomic associations are correlations.
Our point in noting these things is certainly not to denigrate the study by Byars et al. or the other studies cited. These are some very fine studies using state-of-the-art genomic analyses. We simply wanted to explain why we consider such studies less compelling as support for the antagonistic pleiotropy theory than experimental studies done in model laboratory organisms with specific and purposeful manipulation of specific individual genes.
The Engineering of Kidney Organoids Proceeds Apace
This is the organoid era of tissue engineering. Researchers are making earnest progress in establishing the recipes that allow cells to be grown into small, functional tissue sections. They lack a network of capillaries, however, so must be no more than a millimeter or so in thickness in order for nutrients to perfuse sufficiently through the tissue to support all of its cells. Every organ, every tissue has a significantly different recipe, but it is usually something that can be derived from an examination of the biochemistry of embryonic growth, with enough time and funding. Given the large number of different tissues versus the smaller number of research groups working on tissue engineering, this process of discovery will be going on for a while yet. It has taken a great deal of time and effort to produce the first functional organoids, and it will take longer yet to manage complete coverage of the human body.
Today I'll point out a couple of recent articles that focus on kidney organoids specifically. Kidney function is not independent of structure and location as is the case for the liver, so one can't just put kidney organoids into a patient's lymph nodes, as Lygenesis is doing with liver sections. It is nonetheless plausible to transplant some number of kidney organoids into a failing kidney and have them integrate usefully to support overall kidney function. It may be the case that this becomes a widespread mode of therapy before a reliable solution is found for construction of capillary networks in engineered tissue, a challenge that presently blocks the way towards building larger tissue sections and whole organs from a patient's own cells. Or it may not; the future is hard to predict at the best of times, never mind when the research is moving as fast as it is these days.
Engineered mini-kidneys come of age
With organs-in-a-dish a growing success story, research with organoids has increasingly proved its worth. Already, scientists can create organoids that have many of the cell types and complex architectures of human organs such as the kidney, liver, guts, and even the brain. Most organoids grown in vitro, however, have lacked the vasculature to provide the cells with oxygen and nutrients, remove metabolic waste, and facilitate communication between cell types - functions that drive their maturation into working tissue-building blocks.
When it comes to kidney organoids, that shortcoming has kept researchers from reproducing key functions, such as blood filtration, reabsorption, and urine production. A vascularized organoid could better model kidney diseases, enhance renal drug toxicity testing, and ultimately lead to building blocks for replacement therapies. To answer that need, a team of researchers has developed a powerful new approach. By exposing stem cell-derived organoids to fluidic shear stress, they have significantly expanded their vascular networks and improved the maturation of kidney compartments. They hypothesized that fluid flow could help the models form blood vessels from precursor endothelial cells found in growing kidney organoids - and successfully, for the first time, demonstrated that by exposing the organoids to fluid flow, their vascularization and maturation can be enhanced in vitro, rather than in an animal host.
"The vascular networks form close to the epithelial structures that build the glomerular and tubular compartments, and in turn promote epithelial maturation. This integrated process works really like a two-way street. Our method may pave the way to also vascularize other types of organoids, such as the liver organoids."
Researchers develop mini kidneys from urine cells
Thanks to revolutionary developments in stem cell research, scientists can grow mini intestines, livers, lungs and pancreases in the lab. Recently, by growing so-called pluripotent stem cells, they have also been able to do this for kidneys. In a study, researchers used adult stem cells, directly from the patient, for the first time. Cells from urine also proved to be ideal for this purpose. A mini kidney from the lab doesn't look like a normal kidney. But the simple cell structures share many of the characteristics of real kidneys, so researchers can use them to study certain kidney diseases.
"We can use these mini kidneys to model various disorders: hereditary kidney diseases, infections, and cancer. This allows us to study in detail what exactly is going wrong. This helps us to understand the workings of healthy kidneys better, and hopefully, in the future, we will be able to develop treatments for kidney disorders. In the lab, we can give a mini kidney a viral infection which some patients contract following a kidney transplant. We can then establish whether this infection can be cured using a specific drug. And we can also use mini kidneys created from the tissue of a patient with kidney cancer to study cancer."
Signs of Cellular Senescence in Aged Bone Marrow, Contributing to Impaired Generation of Immune Cells
The accumulation of lingering senescence cells with age is apparently there to be discovered in every tissue in the body, and researchers are gathering a great deal of data now that it is generally accepted that these errant cells are one of the causes of aging. The overt signs of cellular senescence in a tissue are much the same throughout the body, even if there may well be significantly different classes of senescent cell still to be categorized. All senescent cells examined to date generate inflammatory, harmful secreted molecules that rouse the immune system, disrupt surrounding cell activities, destructively remodel the extracellular matrix, and more. All of this is a necessary part of regeneration when it takes place over the short term, but when the secretions of senescent cells continue without resolution, over years, the diseases, declines, and chronic inflammation of aging emerge.
In today's open access paper, researchers identify signs of cellular senescence in bone marrow cell populations as a contributing factor to the age-related decline of hematopoietic activity, the very necessary creation of immune and blood cells by hematopoietic stem cells. A reduced supply of new immune cells is one of the major contributing causes of age-related immunosenescence, the faltering of the immune system. The immune system is so fundamental to health that its fall into chronic inflammation and ineffectiveness may be a primary driver of human late-life mortality. Certainly, there is a wide range of evidence linking aspects of immune function with mortality in human cohorts.
What do we do about cellular senescence? We deploy senolytic therapies systemically throughout the body, targeting senescent cells for destruction by triggering apoptosis. The initial set of senolytic compounds used in research and early testing seem moderately effective in mice, clearing up to half of senescent cells from some tissues, and human data is starting to arrive this year. These compounds are cheap and easily obtained by those who don't wish to wait five to ten years for an expensive (and only maybe improved) version to emerge from the regulatory pathway of clinical trials. The research community will be kept quite busy in the years ahead by assessing cellular senescence, and then the removal of senescent cells, in the context of each and every decline of aging. But anyone willing to accept the risks of self-experimentation, after reading through the existing evidence and making an informed decision, can always choose to forge ahead today and try for themselves, to see what happens to their own age-related conditions.
An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program
Hematopoietic stem and progenitor cells (HSPC) can self-renew and differentiate into all blood components thus serving as a reservoir for mature blood cells throughout life. However, as we age, HSPC functionality is impaired with cells displaying a reduced capacity to maintain tissue homeostasis. Hematopoietic stem and progenitor cells reside in the bone marrow (BM) niche, and their function is supported by a variety of both hematopoietic and nonhematopoietic cell types, such as osteoblasts, adipocytes, endothelial, and mesenchymal stromal cells (MSC). Several studies highlighted the key role of MSC in regulating HSPC fate and promoting engraftment of the rare and more primitive hematopoietic stem cells (HSC). Indeed, changes in the cellular composition of the HSC niche during aging contribute to hematologic decline and involve decreased bone formation, enhanced adipogenesis, increased BM inflammation, and altered HSPC-MSC crosstalk.
Senescent cells accumulate during aging and contribute to tissue dysfunction and impaired tissue regeneration. Senescence is also characterized by increased SA-β-Gal activity, persistent DNA damage repair activation, and telomeric attrition. Moreover, senescent cells exhibit transcriptional activation of a senescent-associated secretory inflammatory phenotype collectively known as SASP. The robust secretion of SASP chemokines/cytokines triggers an inflammatory response that could reinforce senescence in a cell-autonomous fashion and be transferred to surrounding cells through paracrine mechanisms, to amplify the senescence response.
To date, the activation of a senescence program in human aged MSC and the interplay between aged MSC and HSPC remain to be elucidated. In this study, we successfully established human BM-derived MSC from young and elderly healthy donors. We investigated the effects of chronological age on MSC properties and found that MSC derived from aged healthy subjects show senescence-like features comprising an enlarged morphology, reduced proliferation capacity, delayed cell cycle progression, and increased levels of SA-β-Gal and lipofuscin. Importantly, we found that aged MSC activate a SASP-like program that contributes in a non cell autonomous manner to impair young HSPC clonogenicity by mediating an inflammatory state in HSPC.
Over the past decade, a growing body of evidence revealed that inflammatory stimuli alter HSPC fate and functionality by affecting HSPC proliferation/quiescence status, differentiation potential, or HSPC-niche interactions. In particular, it has been reported that chronic inflammation drives HSPC myeloid skewing and leads to HSPC exhaustion during aging. Our data indicate that the secretome of aged MSC may as well contribute to boost inflammation in HSPC in a paracrine fashion. However, further investigations are needed to dissect the role of individual SASP factors secreted by aged MSC on HSPC biology and to determine whether chronic exposure of young HSPC to MSC-derived inflammatory molecules may induce paracrine senescence in HSPC as previously described in other settings.
SGLT-2 Inhibitors as Calorie Restriction Mimetics
SGLT-2 inhibitors, or gliflozins, are a newer and still expensive class of anti-diabetic drug. They work by interfering in the trafficking of glucose, preventing the kidney from reclaiming glucose and introducing it back into the bloodstream. The glucose is instead excreted. Analogously to metformin, another anti-diabetic drug, it is proposed that inhibition of SGLT-2 in some ways mimic the effects of calorie restriction, triggering beneficial cellular housekeeping mechanisms that usually only turn on during periods of fasting or low calorie intake. Size of effect and degree of side-effects are always the questions in these matters, however. One should hold back any nascent enthusiasm until able to find reliable answers in the literature.
Evidently, a faction of the research community thinks that metformin has a large enough effect size to run a human trial versus aging, in order to push the FDA into accepting aging as an indication. Following that same line of thinking, these researchers would probably also consider this strategy for one or more SGLT-2 inhibitors. That said, one of the points of using metformin as the lever, to try to make the FDA reconsider aging as a medical condition that can be treated, is that metformin is very widely used and has a long history of use. Not that it is particularly effective in the grand scheme of things. It is hard for the FDA to object to it on any grounds other than aging not being a formally defined and approved medical condition that people are permitted to treat, which is exactly the battle that researchers wish to take place.
SGLT-2 inhibitors induce a fasting state that triggers metabolic benefits
SGLT-2 inhibitors are a relatively new class of diabetes drugs that have shown many benefits for people with type 2 diabetes who have not responded well to previous interventions. Researchers set out to understand how these benefits happen. They found that SGLT-2 inhibitors induce a fasting state in the body without requiring the patient to sharply cut back on food intake.
The researchers studied SGLT-2 inhibitors in a series of animal studies. First, they split the animals into two groups. One ate a normal diet and the other consumed a high fat diet. The high fat diet induced an insulin-resistant, diabetes-like state. They then split the animals into the three different cohorts. One group maintained their original diets. The second group maintained their original diets but also took SGLT-2 inhibitors. The third group matched the weight loss of group two through other methods, to confirm that any beneficial effects seen in group two were a result of SGLT-2 inhibitors and not weight loss in general. The researchers confirmed that the group given the medication saw a large boost to their metabolic processes due to the activation of pathways associated with fasting. "Lowering glucose by this mechanism shifts metabolism toward beneficial pathways that help to reduce fat accumulation in tissues. It causes the liver to think that it's in a fasting state and therefore a lot of pathways and genes are turned on that are similar to what you would see when someone is fasting."
These include pathways typically activated during situations that cause a lack of available nutrients in the body, such as exercise or calorie intake reduction. SGLT-2 inhibitors also blocked a pathway that can cause insulin resistance. The researchers also identified a new hormone mediator of SGLT-2 inhibitor treatment. Mice treated with SGLT-2 inhibitor medication had elevated levels of FGF-21, a hormone known to induce beneficial metabolic effects. Using mice lacking FGF-21, they found that FGF-21 was required for the weight loss and reduced body fat. FGF-21 did not play any role in the reduction of fat deposition in the liver. One mystery still remains, however: what are the specific mechanisms behind the reduction in cardiovascular disease risk observed in humans? This will be an important question for future studies.
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms
SGLT2 inhibitors (SGLT2i) are unique antidiabetic drugs that promote urinary glucose loss and increase the urinary threshold for glucose reabsorption. As a result, plasma glucose levels are reduced and overall glycemic control is improved. Intriguingly, SGLT2i, including canagliflozin (CANA), have recently been shown to reduce cardiovascular and all-cause mortality in type 2 diabetes (T2D) and may improve hepatic steatosis and nonalcoholic fatty liver disease. The cellular actions of SGLT2i are distinct from those of other medications for T2D, such as insulin sensitizers and insulin secretagogues, which reduce blood glucose but increase glucose uptake and promote weight gain. By contrast, SGLT2i act in an insulin-independent manner to cause modest weight loss, promote fatty acid oxidation and ketogenesis, and increase hepatic glucose production, even after a single dose. The unique induction of fatty acid oxidation and ketogenesis by SGLT2i may contribute to not only beneficial outcomes, but also ketoacidosis reported with this medication class.
Here, we utilize an integrated transcriptomic-metabolomics approach to identify molecular mediators of CANA in nondiabetic mice with diet-induced obesity. We demonstrate that CANA modulates key nutrient-sensing pathways, with activation of 5′ AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR), without changing insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis, and increase hepatic and plasma levels of the hepatokine FGF21. FGF21 is an important coordinator of fasting-induced metabolic responses and reduction in adiposity via increasing lipolysis, hepatic fatty acid oxidation, and ketogenesis. Given that these effects mirror many phenotypes induced by CANA, we hypothesized that FGF21 would be required for CANA action. Using FGF21-null mice, we demonstrate that FGF21 is not required for the metabolic switch toward a fasting-like catabolic state but is required to promote lipolysis and reduction in adiposity in response to SGLT2i.
Ccna2 as a Novel Regulator of Cellular Senescence
Given the present wave of investment into the treatment of aging, in both the business and research communities, and given the significant valuations put on the first companies working on senolytic drugs to clear senescent cells, it should come as no surprise to see a land rush underway in the investigation of the biochemistry of cellular senescence. The state of funding for any specific field of research is to a sizable degree steered by what is going on in the world of startups and venture capital. When finding a new mechanism is a potential ticket to valuable intellectual property, a startup company, and production of clinical therapies, then there will be more funding available for researchers involved in the search for mechanisms, and more researchers joining in.
Senescent cells are clearly significant in all aspects of aging, and removing them is proving, in mice at least, to produce robust reversal of aging and age-related disease. Senescent cells, while small in number even in old individuals, produce a potent mix of signals known as the senescence-associated secretory phenotype, or SASP. This SASP generates chronic inflammation, changes the behavior of normal cells for the worse, destructively remodels the extracellular matrix, and more. In some ways it might be considered an actively maintained aspect of aging. Removing senescent cells removes this signaling, and restores tissue function as a result. Other researchers are interested in modulating or suppressing the SASP, but I have to think that this is a much more challenging proposition, given the complexity of SASP signaling.
The open access paper here is an illustrative example of the sort of detailed investigation of the mechanisms of cellular senescence that is taking place today. Some will give rise to efforts to develop new therapies to destroy, prevent, or alter the behavior of senescent cells. This sort of work is spreading and well funded to a degree that would have been unimaginable prior to the noted 2011 demonstration of the relevance of senescent cells to aging. All of this is driven by success in showing that removal of senescent cells reverses aging and age-related disease, and by the significant investment in clinical development that followed.
The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway
It is demonstrated that the presence and progressive accumulation of senescent cells contribute to overall organism aging; senescent cells aggregate in aging tissues have been considered as a causal factor for aging-related disorders. Senescent cells are characterized as irreversible growth arrest, increased senescence-associated β-galactosidase activity, and undergo distinctive phenotypic alterations, including profound chromatin and secretome changes. Research over last three decades has uncovered a variety of signaling pathways that are involved in the regulation of cellular senescence and determine the lifespan in a manner conserved across species, including insulin growth factor 1 (IGF-1) signaling (IIS), rapamycin (mTOR) signaling, and the sirtuin family. Additionally, p53 activation exerts critical roles in modulating cellular senescence and organismal aging. Senescence-induction stressors including DNA lesions, telomere shortening, oxidative stress, and oncogene activation, initially halt cell cycle progression through p53-mediated induction of p21 and finally trigger cellular senescence.
MicroRNAs (miRNAs) are conserved tiny noncoding RNAs generated from endogenous hairpin-shaped precursors, which have emerged as novel and fundamental actors in gene regulation. These small RNA molecules can direct bind to specific sites presented in target messenger RNA (mRNA). As the recognition of target mRNAs mainly depends on the seed region of the mature miRNA, one single miRNA might regulate hundreds of target mRNAs; meanwhile, distinct miRNAs might co-regulated the same mRNA, thus orchestrating a large variety of physiological and cellular processes. Recently, a growing body of evidence has suggested the potential role of miRNAs in modulating the aging process and cellular senescence. In this work, we evaluated the miRNA and mRNA profile in the physiological aging 20-month-old mouse model by high-throughput analysis.
The data showed that various p53 responsive miRNAs, including miR-124, miR-34a and miR-29a/b/c, were up-regulated in the aging mouse compared to the young mouse. Further investigation unraveled that, similarly to miR-34a and miR-29, miR-124 significantly promoted cellular senescence. As expected, mRNA microarray and gene co-expression network analysis unveiled that the most down-regulated mRNAs were enriched in the regulatory pathways of cell proliferation. Fascinatingly, among these down-regulated mRNAs, Ccna2 stood out as a common target of several p53 responsive miRNAs (miR-124 and miR-29), which functioned as the antagonist of p21 in cell cycle regulation.
Silencing of Ccna2 remarkably triggered the cellular senescence, while Ccna2 overexpression delayed cellular senescence and significantly reversed the senescence-induction effect of miR-124 and miR-29. Moreover, these p53 responsive miRNAs were significantly up-regulated during the senescence process of p21-deficient cells; overexpression of p53 responsive miRNAs or knockdown of Ccna2 evidently accelerated the cellular senescence in the absence of p21. Taken together, our data suggested that the p53/miRNAs/Ccna2 pathway might serve as a novel senescence modulator independent of p53/p21 pathway.
More of Just one Component Part of a Proteasome Extends Life in Worms and Flies
Proteasomes are structures the cell, complex assemblies of a number of different proteins, that are responsible for breaking down damaged and excess proteins into small chunks that can be reused as raw materials. As is true of other cell maintenance processes, more proteasomal activity leads to better cell and tissue function, the creation of lesser amounts of downstream damage and dysfunction over time. Aging is modestly slowed. By way of following on from a recent review of upregulated proteasomal activity as a path to the treatment of aging, I'll point out this recent research in which scientists expand upon a very selective way to improve the operation of the proteasome. The production of more copies of just one component part of a proteasome improves overall function to a great enough degree to affect life span in short-lived species, an interesting finding.
Proteasome activity has been shown to decline with age and increasing proteasome function is known to provide benefits to lifespan. Given the multiple roles that the proteasome plays, however, including roles in metabolism, cell proliferation, and cell signaling, among others, discerning which aspects of proteasome function are limiting specifically for aging is necessary for further targeted investigations into the molecular consequences of aging. The major proteolytic activity associated with the proteasome is the chymotrypsin-like activity provided by the β5 subunit, and artificial impairment of only the chymotrypsin-like activity of the proteasome in mice has been shown to be sufficient to cause multiple early aging phenotypes, including shortened lifespans, reduced body weight, altered metabolism, muscle atrophy, and accumulation of ubiquitinated peptides.
The β5 subunit of the proteasome has been shown in worms and in human cell lines to be regulatory. In these models, β5 overexpression results in upregulation of the entire proteasome complex which is sufficient to increase proteotoxic stress resistance, improve metabolic parameters, and increase longevity. However, fundamental questions remain unanswered, including the temporal requirements for β5 overexpression and whether β5 overexpression can extend lifespan in other species.
To determine if adult-only overexpression of the β5 subunit can increase proteasome activity in a different model, we characterized phenotypes associated with β5 overexpression in Drosophila melanogaster adults. We find that adult-only overexpression of the β5 subunit does not result in transcriptional upregulation of the other subunits of the proteasome as they do in nematodes and human cell culture. Despite this lack of a regulatory role, boosting β5 expression increases the chymotrypsin-like activity associated with the proteasome, reduces both the size and number of ubiquitinated protein aggregates in aged flies, and increases longevity. Surprisingly, these phenotypes were not associated with increased resistance to acute proteotoxic insults or improved metabolic parameters.
Aging and Oxidative Signaling in Muscle Tissue
Today's open access review discusses oxidative signaling and damage in aging muscles. All considerations of oxidative molecules in aging are complex, but then nothing in biology is simple. Decades ago, the research community proposed that aging was caused by oxidative damage, but the data that led to that theory of aging was only a small part of the overall story. The original theory has since fallen to the wayside. Yes, there is oxidative damage in old tissues, cell components disrupted by reacting with oxidizing molecules. But cells also use oxidative molecules as signals, and respond to rising levels of oxidation with greater repair efforts. A number of the ways to slow aging in short-lived laboratory species work because they cause a modest increase in the production of oxidative molecules by mitochondria, and any greater level of damage to cellular mechanisms is outweighed by increased activity of cellular maintenance processes.
Mitochondria are the primary source of oxidative molecules, but the process may be fairly indirect, even given the loss of mitochondrial quality and function that is characteristic of aging. In the SENS view of mitochondrial dysfunction, a small fraction of cells become overtaken by broken mitochondria and, as a consequence, export significant volumes of oxidative molecules into surrounding tissue. It is a multi-step process that only begins with mitochondrial damage. Further, consider that levels of oxidative molecules in circulation go hand in hand with inflammation. The immune system declines with age, falling into a state of ineffective chronic inflammatory activity. This may also be an important source of age-related oxidative stress. It is usually challenging to pick apart the degree to which specific mechanisms contribute to aging, as it is hard to alter any one mechanism in complete isolation.
The skeletal muscle is the largest organ in the body comprising ~40% of its mass. It plays fundamental roles in movement, posture, and energy metabolism. The loss of skeletal muscle mass and function with age can have a major impact on quality of life and results in increased dependence and frailty. Age-related decline of skeletal muscle function (sarcopenia) results in strength loss. This loss stems from two major sources, reductions in muscle mass (i.e., quantity) and decrease in its intrinsic capacity for producing force (i.e., quality). Both can be the consequence of several factors, including oxidative stress that is the result of the accumulation of reactive oxygen and nitrogen species (ROS/RNS). The free-radical theory of aging was established more than 60 years ago and has become one of the most studied theories to have been proposed. It is now accepted that this theory and its various spin-offs cannot alone explain the aging process. Nevertheless, huge amounts of data indicate that ROS-mediated aging phenotypes and age-related disorders exist
During physiological homeostasis the overall oxidative balance is maintained by the production of ROS/RNS from several sources and their removal by antioxidant systems, including endogenous or exogenous antioxidant molecules. At physiological concentrations ROS/RNS play essential roles in a variety of signaling pathways. There is an optimal level of ROS/RNS to sustain both cellular homeostasis and adaptive responses, and both too low and too high levels of ROS/RNS are detrimental to cell functions. The skeletal muscle consumes large quantities of oxygen and can generate great amounts of ROS and also reactive nitrogen species. Mitochondria are one of the most important sources of ROS in the skeletal muscle.
The origin of the increased ROS production and oxidative damage is mitochondrial dysfunction with aging, caused by age-related mitochondrial DNA mutations, deletions, and damage>, as well as the impaired ability of muscle cells to remove dysfunctional mitochondria. Oxidative phosphorylation impairment can lead to decreased ATP production and further generation of ROS. Interestingly, aging is associated not only with an increase in oxidative damage but also with an upregulation of antioxidant enzymes in the skeletal muscle. Furthermore, the iron content of the mitochondria in the skeletal muscle increases with aging, amplifying the oxidative damage with the generation of ROS. Increased ROS production, mitochondrial DNA damage, and mitochondrial dysfunction was observed in aged muscles.
The skeletal muscle is highly plastic and shows several adaptations towards mechanical and metabolic stress. Oxidative stressors, like ROS, have long been taken into account as harmful species with negative effects in the skeletal muscle. Proteins are frequently affected by oxidation; thus, elevated ROS levels can cause reversible or irreversible posttranslational modification of cysteine, selenocysteine, histidine, and methionine. Oxidative posttranslational modifications of proteins are characteristic in the aged muscle, such as carbonylation which alters protein function. The oxidative capacity of muscles is strongly associated with health and overall well-being. Enhanced oxidative capacity in the skeletal muscle protects against several pathological phenomena (insulin resistance, metabolic dysregulation, muscle loss with aging, and increased energetic deficits in myopathies). These protective effects are largely associated with enhanced mitochondrial function and elevated numbers of mitochondria, which can protect against cellular stress.
More on Poor Sleep and Levels of Tau in the Brain
You might recall that researchers recently connected poor sleep with raised levels of tau in the brain. Sleep is needed to clear out tau, the amount of which rises during the active use of the brain while waking. Altered forms of tau protein can aggregate in the aging brain to form the neurofibrillary tangles that occur in later stages of Alzheimer's disease, and this might explain some of the known correlation between sleep disruption and neurodegeneration. The study here provides more data on this correlation, linking higher levels of tau with sleep apnea specifically, a common form of sleep disturbance. This is still a correlation in search of definitive proof of causation in humans, however, even if the recent animal study seems fairly compelling on the point of poor sleep causing raised tau levels.
People who stop breathing during sleep may have higher accumulations of the toxic protein tau, a biological hallmark of Alzheimer's disease, in part of the brain that manages memory, navigation, and perception of time. Recent evidence has supported an association between an increased risk for dementia and sleep disruption. That's particularly true for obstructive sleep apnea, which is a potentially serious disorder where breathing repeatedly stops during sleep. However, it remains unclear what could be driving this association.
Using the population-based Mayo Clinic Study of Aging, researchers identified 288 people 65 and older who did not have dementia. Their bed partners were asked whether they noticed if their partners stopped breathing during sleep. Positron emission tomography brain scans of study participants looked for buildup of the toxic protein tau in the entorhinal cortex, which is the part of the brain that is deep behind the nose and susceptible to accumulating tau. The entorhinal cortex stores and retrieves information related to visual perception and when experiences happen. The dysfunctional tau protein forms tangles in the brains of people with Alzheimer's disease, contributing to cognitive decline.
Fifteen percent of the study group, or 43 participants, had bed partners who witnessed sleep apnea. Participants with witnessed apneas had about 4.5 percent higher levels of tau in the entorhinal cortex than those who have not been observed to have apneas during sleep. "Our research results raise the possibility that sleep apnea affects tau accumulation. But it's a chicken and egg problem." Does sleep apnea cause an accumulation of tau, a toxic protein that forms into tangles in the brains of people with Alzheimer's disease? Or does the accumulation of tau in certain areas cause sleep apnea?
Correlating CMV Infection and Markers of Inflammation in Older Individuals
Cytomegalovirus (CMV) is a highly prevalent herpesvirus, and cannot be effectively cleared from the body by the immune system. Nearly everyone is infected by the time old age rolls around. While most people have no obvious symptoms of infection, over decades CMV corrodes the immune system. Ever more cells of the limited number available to the adaptive immune system become uselessly specialized to fight CMV, which leaves ever fewer cells for other tasks. This is one of the contributing causes of immune system aging. A range of studies have demonstrated correlations between CMV infection and markers of immune system decline, such as chronic inflammation. The open access paper noted here is an example of the type.
What to do about CMV? A way to clear it from the body will prevent future issues for those who are young, but won't do much to fix the disruption of the immune system in those already old. Since CMV doesn't appear to cause much damage other than this slow breakage of immune function, it might be better to use targeted cell killing technologies to clear out the adaptive immune cells that are specialized to CMV, and then replace them via some form of cell therapy, or regeneration of the thymus, or another approach with a similar outcome of increased creation of new adaptive immune cells.
Aging has been linked to persistent low-grade systemic inflammation that is characterized by a chronic increase in the levels of circulating pro-inflammatory cytokines, whose presence is highly related to age-related metabolic, cardiovascular, and neurodegenerative diseases. To underscore the importance of pro- and anti-inflammatory homeostasis in aging, and the role of chronic low-grade inflammation in shaping the aging phenotype, a term "inflammaging" has been coined.
Cytokines are signaling molecules possessing unique modulatory functions. Among numerous pro- and anti-inflammatory cytokines, some stand out as influential contributors to age-related differences in health, immunity, and cognition. The tumor necrosis factor (TNF) that plays a key role in several neuroimmune functions is associated with the increased risk for neurodegeneration. IL-6 that is produced mostly by adipose tissue macrophages is elevated in persons of advanced age and people suffering from obesity. IL-10, an anti-inflammatory cytokine, suppresses, in turn, the release of TNF and other inflammatory cytokines. Another prominent pro-inflammatory cytokine, IL-1β is primarily produced by monocytes. Alone or in synergy with TNF, IL-1β affects nearly every cell in the organism.
To complicate matters, the interrelated effects of all surveyed cytokines as well as their influence on immune and neuroendocrine functions can be modified by chronic activity of an infectious agent. A lifelong persistent infection influences immunosenescence and can significantly alter the course of cognitive aging when it acts in conjunction with individual differences in cytokine production and release. Currently, consensus seems to be building around the CMV as such a chronic modifier of cytokine action. CMV exerts significant influence on the aging immune system and thus acts as a driving factor of inflammaging. In older adults, CMV has been linked to increased frailty, accelerated cognitive decline, and an increased risk of cardiovascular and Alzheimer's diseases.
The present study posited four major goals. First, we aimed to measure and characterize the baseline inflammatory status of aged individuals recruited for an intervention study of active aging before starting the cognitive and physical training. Specifically, we assessed main inflammatory and anti-inflammatory biomarkers, such as circulating cytokines. Second, we aimed to explore the influence of gender and CMV-seropositivity on the immune and metabolic markers measured at baseline. Third, we examined the associations among inflammatory and metabolic factors, and assessed whether CMV-seropositivity modifies these relationships. Fourth, we explored the influence of the measured inflammatory factors on the cognitive abilities, such as fluid intelligence, episodic memory, speed, and working memory, in the context of CMV-serostatus and gender.
In the present study we found that both gender and CMV-seropositivity modulate circulating peripheral biomarkers, and that CMV infection modifies associations among the latter. In CMV-seropositive individuals, episodic memory and fluid intelligence correlated negatively with pro-inflammatory IL-6; and episodic memory, fluid intelligence, and working memory correlated negatively with anti-inflammatory IL-1RA. We conclude that both CMV-serostatus and gender may modulate neuroimmune factors, cognitive performance, and the relationship between the two domains.
Fewer Calories, Better Cell Performance
Calorie restriction, reducing calorie intake by 40% or so while maintaining optimal micronutrient intake, is the most reliable way to upregulate all of the cellular maintenance processes that act to improve cell and tissue function. This response to famine evolved very early on in the history of life on our planet, and near all organisms assessed by the research community have a cellular metabolism that operates more efficiently when calories intake is restricted. While everyone should consider trying calorie restriction, given the health benefits it conveys, and given that it costs nothing, it isn't the path to a sizable extension of life span in our species. Efforts to recreate even thin slices of the metabolic response to calorie restriction have proven to be challenging, despite an investment of billions and decades, and even the best present development programs achieve little in the grand scheme of what might be possible given better approaches to the problem of aging. They will only modestly slow aging, not radically change the length of human life.
The number of calories a person eats directly influences the performance of different cells. One experiment on mice shows how a low calorie diet can protect the brain from neuronal cell death associated with diseases such as Alzheimer's, Parkinson's, epilepsy, and cerebral vascular accident (CVA). The mice were divided into two groups. The researchers calculated the average number of calories the group with no caloric restrictions would eat and then fed the other group 40% fewer calories. After 14 weeks, mice belonging to the two groups were given an injection containing a substance known to cause seizures, damage, and neuronal cell death.
While the animals in the group that had no dietary restrictions had seizures, the animals whose calories had been restricted did not. The researchers then studied what occurred in vitro. To do that, they isolated the organelles called mitochondria of the brain cells of the mice, which were also divided into two groups: those that had unrestricted diets and those that had restricted diets. When calcium was introduced to the medium, they noted that uptake was greater in the mitochondria belonging to the group that had ingested fewer calories. Mitochondria are the organelles responsible for energy generation in cells. In the case of the mice subjected to a calorie restricted diet, mitochondria increased the calcium uptake capacity in situations where the level of that mineral was pathologically high.
In the pancreas, caloric restriction has shown to be capable of improving cell response to increased levels of blood glucose. The researchers reached this conclusion after conducting experiments using beta cells that remain in the pancreatic islets and are responsible for producing insulin. Blood serum from mice subjected to a variety of diets, similar to the study on the effects of caloric restriction on neurons, was used to nourish the cells cultivated in vitro. In the cells treated with the serum of animals that ate fewer calories, insulin secretion through the beta cells occurred normally: low when glucose was low and high when glucose was elevated. This did not occur in the animals that ate more calories (and became obese). The experiment showed that there may be a circulating blood factor that acutely modifies beta cell function.
Researchers have again raised the hypothesis of whether the phenomenon is related to the mitochondria, since insulin secretion depends on the availability of ATP (adenosine triphosphate, the molecule that stores energy) in the cell. When they measured oxygen consumption by the two groups of cells, they observed that it was higher in cells that received serum from animals subjected to caloric restriction. Since respiration is responsible for the release of insulin during peak glucose, it was a sign that the cells generated more ATP under that condition. Other experiments have also shown that the mitochondria of cells treated with serum from animals subjected to caloric restriction exchanged more material with each other, which made them more efficient.
Fasting Mimicking Diet as a Treatment for Inflammatory Bowel Disease
Forms of intermittent fasting and calorie restriction are quite effective at reducing inflammation, and the work done on fasting mimicking diets has gone a long way towards quantifying this effect. The goal was to find the 80/20 point on the line between mild calorie restriction and fasting, the most food one can eat and still obtain lasting benefits to metabolic health due to the usual reaction to an extended period of restricted calorie intake. (Which, per that research, is one day at 1000 kcal followed by four more days at 750 kcal per day, provided those calories are in the form of healthy food). Since lowered calorie intake has anti-inflammatory effects, it isn't surprising to see researchers investigating it in the context of inflammatory diseases. The work here is largely interesting for the continued focus on the degree to which the benefits of fasting emerge during the period of increased calorie intake afterwards, rather than during the fast.
A new study reports on the health benefits of periodic cycles of the diet for people with inflammation and indicated that the diet reversed inflammatory bowel disease (IBD) pathology in mice. Results showed that fasting-mimicking diet caused a reduction in intestinal inflammation and an increase in intestinal stem cells in part by promoting the expansion of beneficial gut microbiota. Study authors say the reversal of IBD pathology in mice, together with its anti-inflammatory effects demonstrated in a human clinical trial, indicate that the regimen has the potential to mitigate IBD.
For people with a poor diet, a "once in a while" fix is the periodic use of a low-calorie, plant-based diet that causes cells to act like the body is fasting. Earlier clinical trials allowed participants to consume between 750 and 1,100 calories per day over a five-day period and contained specific proportions of proteins, fats, and carbohydrates. Participants saw reduced risk factors for many life-threatening diseases. "We know that the fasting-mimicking diet is safer and easier than water-only fasting, but the big surprise from this study is that if you replace the fasting-mimicking diet, which includes pre-biotic ingredients, with water, we don't see the same benefits."
In the study, one group of mice adhered to a four-day fasting-mimicking diet by consuming approximately 50 percent of their normal caloric intake on the first day and 10 percent of their normal caloric intake from the second through fourth days. Another group fasted with a water-only diet for 48 hours. The study demonstrated that two cycles of a four-day fasting-mimicking diet followed by a normal diet appeared to be enough to mitigate some, and reverse other, IBD-associated pathologies or symptoms. In contrast, water-only fasting came up short, indicating that certain nutrients in the fasting-mimicking diet contribute to the microbial and anti-inflammatory changes necessary to maximize the effects of the fasting regimen.
The research team observed activation of stem cells and a regenerative effort in the colon and the small intestine, which increased significantly in length only in the presence of multiple cycles of the fasting-mimicking diet. They concluded that fasting primes the body for improvement, but it is the "re-feeding" that provides the opportunity to rebuild cells and tissues. "We've determined that the dietary components are contributing to the beneficial effects; it's not just about the cells of the human body but it's also about the microbes that are affected by both the fasting and the diet. The ingredients in the diet pushed the microbes to help the fasting maximize the benefits against IBD."
Greater Fitness in Old Age Correlates with Greater Ten Year Survival Rates
The research materials here make a good companion piece to a recent study showing that exercise performance, physical fitness in other words, predicts mortality more accurately than age. In the study here, much the same analysis is carried in a different patient population, a sizable group with an average age of 75 at the study outset. Ten years after fitness testing was carried out, mortality data for the study population shows that those of greater fitness were significantly more likely to survive. We shouldn't need any more incentives than already exist to stay active and fit for as long as we can in live, but add this one to the mountain of evidence on the topic.
Doctors use cardiovascular risk factors to help guide decisions about preventive measures and medications. Previous studies have shown that quitting smoking and controlling blood pressure, cholesterol, and diabetes can reduce heart disease risk. However, most studies of cardiovascular risk factors have focused on middle-aged people, leaving a knowledge gap regarding the importance of these risk factors in older people.
The team analyzed medical records from more than 6,500 people aged 70 years and older who underwent an exercise stress test between 1991 and 2009. They assessed fitness based on patients' performance during the exercise stress test, which required patients to exercise on a treadmill as hard as they could. They divided patients into three groups reflecting their fitness based on the number of METs (metabolic equivalents, a measure of exercise workload) they achieved during the test: most fit (10 or more METs), moderately fit (six to 9.9 METs) and least fit (six or fewer METs). For this study, the researchers grouped patients with zero, one, two, or three or more cardiovascular risk factors.
On average, participants were 75 years old when they underwent the stress test. Researchers tracked the patients for an average of just under 10 years, during which time 39 percent of them died. Over this period, the researchers found higher fitness was associated with significantly increased rates of survival. The most fit individuals were more than twice as likely to be alive 10 years later compared with the least fit individuals. In contrast, a patient's total number of cardiovascular risk factors was not associated with their risk of death and patients with zero risk factors had essentially the same likelihood of dying as those with three or more risk factors. The study did not account for any changes in fitness level that the participants may have experienced over time. However, previous studies have suggested that improving fitness can help improve heart health, even late in life.
A Review of DNA Methylation Based Epigenetic Clocks as a Measure of Aging
Epigenetic clocks measure DNA methylation of sites on the genome that are patterned in much the same way in every individual of a given age. DNA methylation is an epigenetic marker that serves to regulate the production of protein from a specific gene. A range of different clocks have been constructed based on weighted assessments of methylation at various points on the genome, and the best of them can measure age quite accurately, to within a few years.
The clocks were built by working backwards from DNA methylation and age data, and it was discovered along the way that people with methylation patterns characteristic of an older age have a worse prognosis for age-related disease and mortality, or have a greater tendency to already exhibit age-related diseases. It is unclear, however, as to what exactly epigenetic clocks really are measuring. Which of the underlying forms of damage and consequent dysfunction, outlined in the SENS rejuvenation research proposals, lead to these DNA methylation changes? Some of them? All of them? No-one can presently say, and that is a challenge if the research community is to use epigenetic clocks to assess potential rejuvenation therapies.
The development of tools to diagnose and predict age-dependent risks has enormous significance in preventing age-related diseases and improving the health status of the elderly. The process of aging results in multiple changes at both the molecular and cellular level, including cellular senescence, telomere attrition, and epigenetic alterations. Among these hallmarks, telomere length, which experiences progressive shortening during replication of somatic cells, is a remarkable characteristic of aging and linked with age-related health status. However, recent evidence has revealed that the correlation between telomere length and age-related outcomes of individuals is low. Thus, investigators are still searching for other biomarkers that can be used in the prediction of age-related outcomes with higher accuracy.
Current studies have indicated that epigenetic changes comprise a significant component of the aging process. Epigenetics refer to the modulation of gene activity without any change in the genomic sequence. Well-studied epigenetic modifications include DNA methylation, histone modification, and non-coding RNA, with changes in dynamic DNA methylation found to be most associated with the aging process. In general, age-dependent changes in DNA methylation include global hypomethylation and region-specific hypermethylation.
Abundant studies have demonstrated a close relationship between DNA methylation and aging and longevity. These findings have impelled researchers to develop age predictors based on the correlation between methylation changes and chronological age. DNA methylation age, evaluated by these predictors, reflects the biological age of a person, which has a close association with individuals' health status and can be changed by multiple risk factors, such as smoking and obesity. Therefore, the difference between DNA methylation age and chronological age may be a promising tool in predicting disease risk and longevity potential in early life.
Burden of Age-Related Disease Varies Broadly Between Regions of the World
Researchers here present an interesting view of the variance in the burden of age-related disease exhibited by populations around the world. Unsurprisingly, the impact of age falls most heavily on those living in the poorest and least developed regions. Modern medicine and the other comforts of technology, for all that they do not directly target the causes of aging, do manage to have a sizable influence on the pace at which aging and age-related disease progresses over a lifetime. The largest gaps are mostly likely due to a combination of sanitation, particulate exposure from fires, and control of pathogens - akin to the difference between today and the 19th century. But the underlying reasons for the differences between wealthier nations, such as Japan versus countries of Western Europe, tend to be harder to pin down.
A 30-year gap separates countries with the highest and lowest ages at which people experience the health problems of a 65-year-old. Researchers found 76-year-olds in Japan and 46-year-olds in Papua New Guinea have the same level of age-related health problems as an "average" person aged 65. These negative effects include impaired functions and loss of physical, mental, and cognitive abilities resulting from the 92 conditions analyzed, five of which are communicable and 81 non-communicable, along with six injuries.
The study is the first of its kin. Where traditional metrics of aging examine increased longevity, this study explores both chronological age and the pace at which aging contributes to health deterioration. The study uses estimates from the Global Burden of Disease study (GBD). Researchers measured "age-related disease burden" by aggregating all disability-adjusted life years (DALYs), a measurement of loss of healthy life, related to the 92 diseases. The findings cover 1990 to 2017 in 195 countries and territories. For example, in 2017, people in Papua New Guinea had the world's highest rate of age-related health problems with more than 500 DALYs per 1,000 adults, four times that of people in Switzerland with just over 100 DALYs per 1,000 adults. The rate in the United States was 161.5 DALYs per 1,000, giving it a ranking of 53rd, between Algeria at 52nd with 161.0 DALYs per 1,000 and Iran at 54th with 164.8 DALYs per 1,000.
Using global average 65-year-olds as a reference group, researchers also estimated the ages at which the population in each country experienced the same related burden rate. They found wide variation in how well or poorly people age. Ranked first, Japanese 76-year-olds experience the same aging burden as 46-year-olds in Papua New Guinea, which ranked last across 195 countries and territories. At 68.5 years, the United States ranked 54th, between Iran (69.0 years) and Antigua and Barbuda (68.4 years).
Proposing the IMM-AGE Metric to Measure the Aging of the Immune System
Determinations of biological age based on ever more detailed measurements of human cellular biochemistry are known as clocks. Biological age is distinct from chronological age, as different people age at somewhat different rates. Aging is an accumulation of cell and tissue damage and the consequences of that damage; more damage means a higher biological age. The best known clock examples are the well known varieties of epigenetic clock, based on patterns of DNA methylation that decorate the genome. In recent years, researchers have been rapidly developing other sorts of clock, using other measures of cellular biochemistry and metabolism. The one here is an example of the type, focused on immune system function.
The immune system is the critical function in the body for managing health. It is a complex system with hundreds of different cell-types. Until now, no metric had existed to quantify an individual's immune status. New data, while requiring further development, describes a metric (called IMM-AGE) by which we can accurately understand a person's immune status, providing increased information for accurate prediction and management of risks for disease and death.
This new capability will have drug development implications: Given the importance of immune status in vaccine response, this new data could play a significant role in both the design of future vaccine trials and in re-evaluating past vaccine trials. Moreover, this new metric for immune aging could see chronological age augmented by "immune age" as a way of improving drug development programs - providing for enhanced clinical trial entry/exclusion criteria that can elicit a more homogenous response and greater likelihood of success.
The researchers developed their unique data by following a group of 135 healthy volunteers for nine years, taking annual blood samples which were profiled against a range of 'omics' technologies (cell subset phenotyping, functional responses of cells to cytokine stimulations and whole blood gene expression). This captured population- and individual-level changes to the immune system over time, which when analyzed using a range of novel, immune aligned, machine learning analytical technologies, enabled identification of patterns of cell-subset changes, common to those in the study, despite the large amount of variation in their immune system states. The data and metrics generated was then validated against a cohort of more than 2,000 patients from the Framingham Heart Study.