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- On Giving Tuesday, Help to Build a Future in which Aging is Controlled and Age-Related Diseases No Longer Exist
- Future Directions for the Senescence Field
- Additional Evidence for Lymph Node Degeneration to be an Important Obstacle for Attempts at Thymus Rejuvenation
- Mitochondrial Dysfunction Causes Telomere Attrition
- Delivering Klotho to Old Mice Partially Reverses Loss of Muscle Regenerative Capacity
- Resistance Training Correlates with Reduced Risk of Cardiovascular Disease
- Can Systems Analysis Approaches Provide Insight into the Mechanisms of Aging?
- Ssk Upregulation Extends Improves Intestinal Function and Extends Life in Flies
- Reviewing Recent Progress in Investigations of Calorie Restriction and Fasting
- Another Study Demonstrating that Older People Fail to Exercise Sufficiently
- Alzheimer's Subtypes Differentiated by How and Why Amyloid-β Accumulates
- MRI Scans Predict Development of Dementia a Few Years in Advance
- A DNA Vaccine Reduces Both Amyloid-β and Tau Aggregates in Mice
- Bioengineered Intervertebral Discs are Implanted Successfully in Goats
- Atrophy of the Thymus Accelerates the Progression of Atherosclerosis
On Giving Tuesday, Help to Build a Future in which Aging is Controlled and Age-Related Diseases No Longer Exist
Giving Tuesday is just a few days away, the better sibling of earlier days of mandated commerce. Whatever your thoughts on top-down collectivism, there are worse things in the world than a successful movement to prompt people into thinking about the causes they support in principle, and encourage them to make that support material. Philanthropy is a very necessary part of our society, and particularly in the case of technological progress. Established sources of funding for medial research and development, even those we might think of as having an appetite for risk, such as venture capital funds, are in fact very conservative. The greater the pool of funds, the more conservative and risk-averse its controllers. But all new lines of research, all first attempts at development, are by nature highly risky endeavors, and thus there is very little funding for them.
The world is awash in money looking for a home, but next to none of those resources flow towards the high-risk, high-reward projects that will produce the next generation of medical technology. In the case we are interested in, that next generation means rejuvenation therapies capable of repairing and reversing the known root causes of aging. The foundation technologies for rejuvenation, those outlined more than fifteen years ago in the SENS proposals, still largely languish. Despite the successes that our broader community has achieved since then, such as the current excitement and investment in senolytic therapies to destroy senescent cells, most of these lines of work are still poorly funded. Few groups are focused directly on the production of therapies in these underfunded parts of the field.
The only way that lagging fields of research and development move forward in earnest is through philanthropy. Through people like us helping to provide the resources that can power organizations like the SENS Research Foundation and Methuselah Foundation, to give them the ability to fund the right programs, to bring that work up to the level at which the world will notice and large, conservative funding organizations start to join in. Our support has enabled initiatives that have been enormously successful in past years, given the modest size of our community. We have already changed the world by helping to seed research programs that will blossom into rejuvenation therapies - but there is much more yet to be accomplished. We have started. We must now continue towards to goal of a comprehensive toolkit of rejuvenation therapies that can repair all of the cell and tissue damage that causes aging.
So this Giving Tuesday, when you think about how you appreciate the work of the non-profit organizations in our community, then make that appreciation material. Make a donation to support continued progress towards working rejuvenation therapies, and longer, healthier lives for all.
Future Directions for the Senescence Field
Today's open access paper is, I think, chiefly interesting for the later section in which the authors ponder future directions for the treatment of aging via means of destroying or manipulating the activity of senescent cells. The accumulation of senescent cells is one of the root causes of aging. The creation of senescent cells happens constantly in the undamaged and fully functional tissues of young people, a tiny fraction of these senescent cells manage to evade destruction and linger to cause issues, and given enough time that fraction will grow large enough to kill you. Cellular senescence isn't the only harmful cause of aging, of course. As things stand, senescent cells speed the death that emerges from other forms of damage, and never have the chance to be the cause of death in and of themselves. Aging is a collaborative murder, carried out via the interaction of many distinct processes.
Selective destruction of senescent cells appears to work well as an approach to remove their contribution to aging. There are comparatively few such cells, no-one has yet found a population of senescent cells that is sufficiently vital to keep around, and numerous methods of destruction either already exist and are under development. By all measures assessed so far, old mice are greatly improved following removal of even a fraction of their senescent cells. To my eyes at least, the path to the future of the senescence field is the very simple one of finding ever more efficient ways to remove these errant and unwanted cells. The first approaches, even as they produce outstanding results in animal studies, are far from perfect. Removing only half of the senescent cell burden leaves half of the job undone, half of the benefits left to be claimed.
Some researchers disagree with the sole focus on destruction, however. They wish to pursue modulation of the bad behavior of senescent cells, or find ways to undo the transition into senescence. I have to think that this is a much harder road to more limited benefits, as well as offering greater risks to patients as damaged cells are pushed into renewed labors. Cellular senescence serves a purpose, in that it is protective against cancer, aids in regeneration from injury, and is a vital part of the replication limit imposed on most cells. In all such cases, the requirement for senescence and its characteristic behaviors is brief and the senescent cells can and should be removed afterwards. If a cell has become senescent due to DNA damage, with the accompanying risk of cancer, then better to remove it than to try to restore it, at least at our present level of technological sophistication.
The senescent cell epigenome
When cellular senescence was first characterized in in vitro cell culture, links to tissue and organismal aging were proposed. Critics of cellular senescence questioned its relevance to in vivo aging, their possibility of being an artefact and the inevitable lack of senescence despite normal aging in lower organisms. Senescence as a pro-aging phenomenon gained popularity with the discovery of biomarkers such as p16 and beta-galactosidase in multiple aged tissues. Mechanistically, the idea of senescent cells being causal in chronic inflammation characteristic of aging, also gained momentum with the discovery of the senescence-associated secretory phenotype (SASP).
The senescence field came of age with four major milestones, (a) two proof-of-concept studies showed major improvement in healthspan and lifespan in mice by the targeted ablation of senescent cells, (b) development of small molecule senolytics as a therapeutic strategy for clearing senescent cells, (c) demonstration that senolytics improve physiological function and lifespan in aged mice and (d) the success of senolytics in pre-clinical studies of a range of age-related conditions. Below, we discuss potential alternatives to senolytics that can deploy epigenetic proteins as "switches" to turn on/off specific pathways in senescent cells for their effective elimination.
Despite the overwhelming success of senolytics, fundamental concerns about specificity and safety prevail. Additionally, the potential benefit of senolytics in treating age-related disease remains to be tested. A second class of molecules that have shown promise in anti-aging rejuvenation therapies is SASP inhibitors. The concept of annihilating the pro-aging arm of senescent cells while preserving the anti-tumor arm is a very attractive treatment option in the elderly who have a high incidence of cancer. Both rapamycin and metformin have shown anti-SASP effects and are on the road to clinical trial for aging. Alternatively, epigenetic enzymes that play a key role in turning on SASP genes (MLL1 and BRD4) can be inhibited by small molecules to prevent its deleterious effects.
Autophagy is a self-degenerative process that clears and recycles damaged cellular components. In a seminal publication, it was reported that basal autophagy is essential to maintain the stem-cell quiescent state while preventing senescence of muscle satellite cells in mice. Furthermore, autophagy declines during aging, calorie restriction activates autophagy, and dysfunctional autophagy is evident in Alzheimer's disease pathology. Thus, boosting general macroautophagy (non-selective) is a viable anti-aging avenue. The challenge of autophagy-promoting strategies however comes from observations that autophagy of "nuclear" substrates might in fact contribute to senescence, aging, and inflammation.
Senescent cells are naturally cleared by innate immune mechanisms with the macrophage playing a central role. However, immune cells themselves undergo progressive decline in function (termed immunosenescence) that actively contributes to senescent cell accumulation. Furthermore, it has been proposed that subsets of senescent cells become resistant to immune-mediated clearance. Therefore, epigenetic interventions that boost immune surveillance in aged tissues or antibody-based therapies that revert the immune-resistance of senescent cells may also be future rejuvenation strategies.
The principles of regenerative medicine can be applied in aging and age-related disease. Expression of pluripotency factors in senescent cells have been shown to allow cell cycle entry with reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism. Additionally, their expression in mice has also shown amelioration of a panel of age-related phenotypes. Epigenetic factors that can potentiate reprogramming can be used to rejuvenate senescent/aged cells. However, it is important to be cautious with regenerative therapy in the elderly because of its potential to be pro-tumorigenic.
Other potential epigenetic therapies
The emerging conceptual themes that arise from the observations are (a) a gradual euchromatinization of the genome, (b) loss or disorganization of constitutive heterochromatin due to (c) breakdown of the nuclear lamina and changes in nuclear morphology and (d) loss of spatial organization of the genome. These large-scale changes manifest in profound transcriptional alterations that ultimately activate programs such as SASP and contribute to transcriptional noise. Systematic screens for epigenetic factors will likely yield potential candidates that can be targeted to prevent or reverse the detrimental effects of senescence.
Additional Evidence for Lymph Node Degeneration to be an Important Obstacle for Attempts at Thymus Rejuvenation
The thymus atrophies with age, and since its primary function is to support the maturation of T cells, this means that the supply of new T cells, fresh and ready for action, also declines with age. This contributes greatly to immunosenescence, the progressive age-related failure of the immune system to respond to pathogens and destroy damaged or malfunctioning cells. Numerous research groups are attempting to restore the thymus to youthful size and activity, and thus also restore the supply of T cells, and reverse loss of immune function. A wide variety of approaches are under development, from gene therapies and small molecules aimed at the controlling proteins of thymic activity to tissue engineering and cell therapies.
Thymic rejuvenation is only one aspect of comprehensive restoration of youthful immune function. The hematopoietic stem cell population in bone marrow that generates immune cells becomes damaged and declines in function with age. These calls must be replaced in a manner that is far safer, more reliable, and cost-effective than current hematopoietic stem cell transplants. The accumulated debris of years of malfunctioning, damaged, and senescent immune cells must be safely destroyed. Further, of late the compelling argument has been made that lymph nodes become so dysfunctional with age that they will block the benefits of raised numbers of effective immune cells. Lymph nodes play a vital role in the immune response, acting as a sort of coordination point for immune cells to talk to one another. Thus regeneration of lymph nodes appears to be on the agenda as well.
Each of those tasks is big enough to build a company around, but all need to be accomplished at the end of the day. The way in which these compound development projects typically work is that every company involved works on achieving success in one line of work, even though the scope of benefits is reduced by the absence of the other programs. That success can then be used to generate interest and funding enough to start tackling those other programs. Sometimes this takes an industry and many companies collaborating, sometimes a single company can work its way through over the years. The way forward is at least fairly clear.
The open access paper here is effectively a call to arms on the lymph node dysfunction issue, the formally published results from scientific work publicized last year. The researchers use one of the weaker approaches to thymic rejuvenation in order to demonstrate that raised amounts of new T cells emerging from the thymus fail to help the immune response to infection when lymph nodes are dysfunctional in older animals. In this respect, the proposition is that there are three limiting factors here, that arise at differing times and to differing degrees across the course of aging, rather than only two: (a) hematopoietic stem cell output of immune cells, (b) thymic activity to allow those immune cells to mature, and (c) the integrity of lymph nodes to allow immune cells to coordinate and act.
One of the more interesting aspects of lymph node aging is that it involves significant amounts of fibrosis, the replacement of correct tissue structure with scar-like structures. In recent years fibrosis has been strongly connected with cellular senescence and the detrimental effects these cells have on regeneration and the extracellular matrix in their surroundings. Removal of senescence cells is a going concern, shown to improve many measures of function in older animals. So when approaching the lymph node challenge the first thing to try is probably the established senolytics, drugs that can selectively destroy a fraction of senescent cells. I believe that no-one in the senescence community has yet earnestly looked into what happens in the lymph nodes of animals treated with senolytics, but that will change soon enough.
Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates
The thymus undergoes age-related involution, that includes progressive loss of thymic epithelial and hematopoietic lineage cellularity, an increase in adiposity, and reduced T-cell output. In the periphery, fewer naïve T cells are available, and the old T-cell compartment is less able to respond to infections and cancer. This is believed to contribute to increased vulnerability of older adults to emerging and reemerging infections. More recent evidence suggests that secondary lymphoid organ (SLO) organization and structure also undergo changes with increased age, and the impact of these changes upon naïve T-cell survival and function is beginning to be understood.
A "holy grail" of T-cell aging research is to achieve functional rejuvenation of T-cell function. Early experiments with surgical castration have shown that transient thymic rejuvenation is possible, as measured by increased thymic volume and cellularity. Similar results have since been obtained using pharmacological sex steroid blockade as well as injection of growth factors. While some of these studies have shown some improvement in peripheral immune function in treated mice, the ultimate tests of functional immunity in the face of microbial challenge were not performed. Therefore, the question remains how well thymic rejuvenation improves the peripheral T-cell pool with aging, and whether it confers improved protection against infection.
To address this question, we examined the effects of (a) keratinocyte growth factor (KGF) administration in mice and nonhuman primates, or (b) sex steroid ablation (SSA) in mice using an antagonist of the luteinizing hormone-releasing hormone receptor, degarelix (Firmagon). Despite robust thymic rejuvenation in response to both interventions, we found no evidence of improved peripheral T-cell maintenance. KGF-treated old mice were not more effective at mounting CD8 T-cell responses to, or clearance of, Listeria monocytogenes. Similarly, degarelix did not improve CD8 T-cell responses to, or survival of old mice following challenge with, West Nile virus (WNV).
While rejuvenated thymi produced substantial numbers of recent thymic emigrants (RTE), these RTE did not significantly contribute to T-cell populations in the SLO of old mice compared to adults. We further found that old lymph nodes exhibited considerable fibrosis and degeneration of structure. These data indicate that restoration of thymic function by itself may not be sufficient to improve the immune response in elderly and suggest that interventions to simultaneously alleviate defects in aging SLO may need to be considered when designing strategies to improve immune response in older organisms.
Mitochondrial Dysfunction Causes Telomere Attrition
I have long argued that reduction in average telomere length with age is a downstream measure of aging, not an upstream cause of aging. Telomeres are the caps of repeated DNA sequences found at the end of chromosomes. A little is lost with each cell division, and when telomeres get too short then the cell become senescent and is destroyed. This mechanism limits the number of times a cell can replicate. The vast majority of our cells are somatic cells that are limited in this way. A tiny number of stem cells can maintain lengthy telomeres via use of the telomerase enzyme and thus divide indefinitely. This is how near all multicellular species keep the risk of cancer low enough to survive long enough to reproduce - only a tiny minority of cells are privileged with unlimited replication capacity.
Average telomere length is thus a measure of how rapidly cells divide and die, combined with how rapidly stem cells divide to deliver new daughter somatic cells with long telomeres to make up the losses. Stem cell function declines with age, a result of both molecular damage direction and indirectly via a changing balance of signals that are reactions to that damage. Fewer daughter somatic cells with long telomeres means shorter average telomere lengths in tissues. Telomere length is thus a measure of declining function.
Nonetheless, many groups are very enthusiastic about using telomerase to artificially lengthen telomeres. This extends healthy life span in mice, despite the fact that it is a matter of putting damaged cells back to work. This outcome, alongside the fact that stem cell therapies are beneficial, suggests that evolution has not produced a fine balance between declining function and cancer risk. There is some room for cells to act more vigorously in later life than they will do naturally. This is not, however, a reversal of aging. It is pushing the damaged engine harder. If we can, then let us take the benefits offered, but cautiously.
The research here is most interesting, as it causally links loss of mitochondrial function to telomere attrition via a mechanism that doesn't appear to have to involve telomerase activity. Mitochondria are the power plants of the cell, vital in the sense that they produce the chemical energy store molecules needed to power cellular activity. Failing mitochondrial function is implicated in age-related diseases of the energy-hungry brain and muscles, for example, though the degree to which this decline results from inherent damage in mitochondria versus reactions to damage elsewhere in tissues is an open question. Being able to demonstrate that age-damaged mitochondria are responsible for some fraction of telomere attrition puts a different twist on benefits in mice that result from lengthening those telomeres again. I'd like to see a paper with more of a focus on stem cells and somatic cells in this context rather than cancer cells, however.
hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction
Here we report an epigenetic mechanism by which mitochondrial dysfunction plays a role in inducing telomere attrition through acetyltransferase activity of hnRNPA2. Our results show that hnRNPA2 mediated H4K8 acetylation is a signal for telomere shortening. Additionally we provide evidence that alterations in the telomere length in response to mitochondrial dysfunction is dependent on histone acetylation status because mutant hnRNPA2 proteins, which show vastly reduced histone acetylation activity, cause a rescue of telomere length. This is in agreement with previous reports in cancer cells where telomere histone acetylation has been shown to correlate with telomere length. While our results show the causal role of mitochondrial dysfunction in telomere length maintenance by a novel epigenetic mechanism, prior studies have reported mitochondrial dysfunction as the result of telomere attrition, providing evidence for the close association between mitochondrial functions and telomere dynamics.
Mitochondria are highly susceptible to damage from numerous factors including free radicals, environmental chemicals, radiation exposure, and lipid peroxides produced by defective electron transport chain, the hypoxic environment prevalent in solid tumors and defective mtDNA transcription and replication machinery. These cellular and environmental stressors can cause mitochondrial defects such as reduction in mtDNA copy number, mtDNA mutations/deletions and impaired electron transport chain activity. In fact, defects in OXPHOS and accumulating mtDNA mutations are associated with aging and age-associated cancers. A common pathological feature of both of these diseases is shortened telomere DNA leading to DNA damage.
The consequence of telomere shortening in aging and cancer remains unclear. The prevailing view is that in aging, telomere shortening continues until cells senesce and finally die, while in cancer, the attrition stops when the telomere DNA reaches a critical length, and cells continue to divide and proliferate. It is suggested that induced telomerase activity in cancer cells is a critical factor, which prevents cell senescence and promotes tumor proliferation. It may be seemingly contradictory that mitochondrial dysfunction in immortalized cancer cells induces a proliferative phenotype in spite of mitochondrial stress induced telomere attrition. In a recent study tested the telomerase activity in these cell lines and found that mitochondrial stress induced signaling simultaneously activates telomerase in these cells. This provides a plausible explanation for these cells to maintain the critical telomere length for resisting senescence. In support, in IMR-90 cells, which do not express telomerase, we show that induction of mtDNA depletion results in hnRNPA2 activation and telomere shortening resulting in senescence. This suggests that the rescue of telomere length is possibly attributable to the reduced telomere histone acetylation but not due to activation of telomerase.
Delivering Klotho to Old Mice Partially Reverses Loss of Muscle Regenerative Capacity
Klotho is one of the better known longevity-associated genes. More klotho improves function and slows measures of aging in mice, and there is suggestive evidence for the same to be true to some degree in humans. The effect on life span is likely to be smaller in our comparatively long-lived species, unfortunately. This is true of all of the approaches to slowing aging for which there is data in both mice and humans to directly compare. Changes to the operation of metabolism that influence the pace of aging are subject to a long history of evolutionary pressures that lead to much greater plasticity of lifespan in response to environmental circumstances in short-lived species. Consider seasonal famines for example; a season is a sizable fraction of a mouse life span, but not of a human life span, and so only the mouse evolves the ability to live much longer when subject to stresses of this nature.
Much of the recent work on klotho has focused on its positive influence on the function of the brain. Delivering klotho improves cognitive function in both young and old animals, and thus this approach to therapy isn't just a case of producing a tool to mitigate some of the mental declines of aging, even though it is very much the case that levels of klotho diminish in later life. Klotho therapies, once developed, might be an enhancement that could benefit all people.
Klotho doesn't just act in the brain, however. As the research noted here makes clear, klotho also plays an important role in the regeneration of muscle tissue. This is the result of long years of investigation into how klotho interacts with the rest of cellular biochemistry in muscles; it is a complex business. The open access paper below outlines evidence to suggest that mitochondrial function is the critical mechanism by which klotho provides benefits. Mitochondria are the power plants of the cell, providing energy stores needed for cellular function. Loss of mitochondrial function is implicated in numerous aspects of aging, particularly in energy-hungry brain and muscle tissues. So it may well be that a sizable fraction of klotho's benefits in the brain are also mediated by greater mitochondrial function.
'Longevity Protein' Rejuvenates Muscle Healing in Old Mice
One of the downsides to getting older is that skeletal muscle loses its ability to heal after injury. New research implicates Klotho, both as culprit and therapeutic target. In young animals, Klotho expression soars after a muscle injury, whereas in old animals, it remains flat. By raising Klotho levels in old animals, or by mitigating downstream effects of Klotho deficiency, the researchers could restore muscle regeneration after injury. "We found that we were able to rescue, at least in part, the regenerative defect of aged skeletal muscle. We saw functional levels of muscle regeneration in old animals that paralleled those of their young counterparts, suggesting that this could potentially be a therapeutic option down the road."
Suspecting that Klotho acts through mitochondria dysfunction, the researchers gave Klotho-deficient animals a mitochondria-targeting drug called SS-31, which currently is in phase III clinical trials. Treated animals grew more new muscle tissue at the site of injury compared to untreated controls, and their strength after recovery rivaled that of genetically normal mice. Similarly, injecting Klotho into older animals a few days after injury resulted in greater muscle mass and better functional recovery than their saline-treated counterparts. Normal, healthy mice did not benefit from SS-31 after injury. Clinically, these findings could translate to older adults who either sustained a muscle injury or underwent muscle-damaging surgery. Giving them Klotho at the appropriate timepoint could boost their muscle regeneration and lead to a more complete recovery.
Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration
In this study, we tested the hypothesis that age-related declines in α-Klotho drive dysfunctional muscle progenitor cell (MPC) mitochondrial bioenergetics, ultimately resulting in an impaired tissue regeneration. Our findings demonstrate that young skeletal muscle displays a robust increase in local α-Klotho expression following an acute muscle injury with transient demethylation of the Klotho promoter. However, aged muscle displays no change in Klotho promoter methylation and no increase in α-Klotho expression following injury.
Levels of α-Klotho in MPCs derived from aged mice are decreased relative to those of young animals, and genetic knockdown of α-Klotho in young MPCs confers an aged phenotype with pathogenic mitochondrial ultrastructure, decreased mitochondrial bioenergetics, mitochondrial DNA damage, and increased senescence. Further supporting a role for α-Klotho in skeletal muscle vitality, mice heterozygously deficient for Klotho (Kl+/-) have impaired MPC bioenergetics that is consistent with a defective regenerative response following injury, but the regenerative defect of Kl+/- mice is rescued at the cellular and organismal level when mitochondrial ultrastructure is restored through treatment with the mitochondria-targeted peptide, SS-31.
Finally, we demonstrate that systemic delivery of exogenous α-Klotho rejuvenates MPC bioenergetics and enhances functional myofiber regeneration in aged animals in a temporally dependent manner. Together, these findings reveal a role for α-Klotho in the regulation of MPC mitochondrial function and skeletal muscle regenerative capacity.
Resistance Training Correlates with Reduced Risk of Cardiovascular Disease
As one of many continuations of recent efforts to quantify the benefits of various forms of exercise, researchers here find an association between resistance training and reduced risk of cardiovascular disease. The association is fairly binary; people undertaking any meaningful degree of resistance training show the benefit, and the size of the benefit doesn't increase with more resistance training. That might make us suspicious regarding the direction of causation. If the association exists because only more robust older individuals tend to undertake resistance training, then the absence of a curve of increasing benefits for greater time spent in training is the expected outcome. The important determinant in that case is the capacity for resistance training. That said, there is plenty of other evidence to suggest that resistance training does in fact provide benefits, a situation analogous to that for aerobic exercise.
Lifting weights for less than an hour a week may reduce your risk for a heart attack or stroke by 40 to 70 percent, according to a new study. Spending more than an hour in the weight room did not yield any additional benefit, the researchers found. The results - some of the first to look at resistance exercise and cardiovascular disease - show benefits of strength training are independent of running, walking, or other aerobic activity. In other words, you do not have to meet the recommended guidelines for aerobic physical activity to lower your risk; weight training alone is enough.
Reseaerchers analyzed data of nearly 13,000 adults in the Aerobics Center Longitudinal Study. They measured three health outcomes: cardiovascular events such as heart attack and stroke that did not result in death, all cardiovascular events including death and any type of death. Resistance exercise reduced the risk for all three.
Much of the research on strength training has focused on bone health, physical function and quality of life in older adults. When it comes to reducing the risk for cardiovascular disease, most people think of running or other cardio activity. Weight lifting is just as good for your heart, and there are other benefits. Using the same dataset, researchers looked at the relationship between resistance exercise and diabetes as well as hypercholesterolemia, or high cholesterol. The two studies found resistance exercise lowered the risk for both. Less than an hour of weekly resistance exercise (compared with no resistance exercise) was associated with a 29 percent lower risk of developing metabolic syndrome, which increases risk of heart disease, stroke and diabetes. The risk of hypercholesterolemia was 32 percent lower. The results for both studies also were independent of aerobic exercise.
Can Systems Analysis Approaches Provide Insight into the Mechanisms of Aging?
Given enough data from enough old people, to what degree could modern approaches to information processing be used to derive useful information about the underlying mechanisms of aging? Such as which of the varied collection of causes and consequences involved in the biochemistry of aging are more important, how they are connected to one another, and so forth. On the one hand it seems plausible that something can be learned here, but on the other hand it seems unlikely to be as effective an approach as selectively interfering in specific mechanisms in order to observe the outcome in animal studies.
So far near all of the demonstrated approaches capable of slowing aging have involved upregulation of stress responses, something that changes near all aspects of metabolism and influences near all aspects of aging. That makes it hard to draw conclusions about the structural makeup of aging, how its distinct processes are weighted, and how they interact. But with the advent of narrow approaches such as senolytic drugs that destroy senescent cells, it becomes possible for the first time to easily affect just one aspect of aging. It will be interesting to observe the data resulting from analytical studies as they arrive in the years ahead.
Aging in most species, including humans, manifests itself as a progressive functional decline leading to the exponential increase in death risk from all causes. The mortality rate doubling time is approximately 8 years. Age-independent mortality mostly associated with violent death and infectious diseases has been progressively declining over the last century, mainly due to universal access to modern medicine and sanitation. The risks of death associated with the most prevalent age-related diseases remain very low at first, increase exponentially and dominate after the age of about 40. The incidence rates of the specific diseases, such as cancer or stroke, also accelerate after this age and double at a rate that closely tracks mortality acceleration. It is therefore, entirely plausible to think there is a single underlying driving force behind the progressive accumulation of health deficits, leading to the increased susceptibility to disease and death. This force is aging.
Although we have come to expect that physical decline is a natural consequence of aging, there is no natural law that dictates the exponential morbidity and mortality increase we observe among human populations. It is possible for death risks to increase very slowly, stay constant for extended periods, or even decline with age. Naked mole rats and the growing number of bat species are now recognized as examples of mammals that exhibit the lack of detectable mortality acceleration, or negligible senescence. Formally, this means that the mortality rate doubling time could be arbitrarily large.
We have suggested that the mortality acceleration may vanish depending on modifiable parameters, such as DNA repair or protein homeostasis maintenance efficiency, and should be, in principle, subject to manipulation. We propose to combine big data from large prospective observational studies with analytical tools borrowed from the physics of complex dynamic systems to "reverse engineer" the underlying biology behind the Gompertz law of mortality variables. This approach may yield mechanistic predictive models of aging for systematic discovery of biomarkers of aging and identification of novel therapeutic targets for future anti-aging therapies.
Ssk Upregulation Extends Improves Intestinal Function and Extends Life in Flies
The snakeskin (Ssk) gene joins the short list of genes that can be manipulated to either reduce and extend life span in a short-lived laboratory species, flies in this case. Loss of Ssk causes intestinal dysfunction, and in flies the intestine is probably the most important organ in late life decline and mortality, much more so than is the case in mammals. Increasing Ssk in old flies reduces all of the features of intestinal dysfunction normally associated with aging, and the flies live longer as a result. The composition of gut microbial populations appears to be important in this effect, but it is unclear as to how exactly Ssk is mediating those populations, even given a fair amount of research linking changes in microbial populations with the cellular mechanisms that Ssk is known to be involved in.
Occluding junctions play critical roles in epithelial barrier function, restricting the free diffusion of solutes between cells, as well as in the regulation of paracellular transport. In vertebrates, the occluding junctions are called tight junctions and their functional roles are well characterized. A functionally analogous structure, called the septate junction (SJ), exists in invertebrates, such as the smooth SJs (sSJs) of Drosophila, which are found in endodermally derived epithelia, such as the midgut.
Age-related alterations in intestinal epithelial junction expression and localization have been observed in flies and mammals, yet the causal relationships between changes in occluding junction function, intestinal homeostasis, and organismal aging are only beginning to be understood. Age-onset microbial dysbiosis is tightly linked to intestinal barrier dysfunction in both flies and mice. Critically, however, the question of whether manipulating intestinal occluding junction expression can delay age-onset dysbiosis and/or positively affect lifespan has not been addressed in any organism.
In this study, we show that Snakeskin (Ssk), an sSJ-specific protein, plays an important role in controlling the density and composition of the gut microbiota and that upregulation of Ssk during aging can prolong Drosophila lifespan. More specifically, loss of intestinal Ssk in adults leads to rapid-onset intestinal barrier dysfunction, changes in gut morphology, altered expression of antimicrobial peptides (AMPs), and microbial dysbiosis. Critically, we show that these phenotypes, including intestinal barrier dysfunction and dysbiosis, can be reversed upon restored Ssk expression.
Consistent with a critical role for intestinal junction proteins in organismal viability, loss of intestinal Ssk in adult animals leads to the rapid depletion of metabolic stores and rapid death. Importantly, restoring Ssk expression in flies showing intestinal barrier dysfunction prevents early-onset mortality. Moreover, intestinal upregulation of Ssk in normal flies protects against microbial translocation, limits age-onset dysbiosis, and prolongs lifespan. Our findings support the idea that occluding junction modulation could prove an effective therapeutic approach to prolong both intestinal and organismal health during aging in other species, including mammals.
Reviewing Recent Progress in Investigations of Calorie Restriction and Fasting
A great deal of present day research is in one way or another focused on forms of lowered calorie intake. There are those who seek to fully map the mechanisms by which calorie restriction and intermittent fasting improve health and extend life significantly in short lived species. There are those who are trying to sufficiently quantify the benefits to be able to produce robust calorie-specific medical diets. There are those who are trying to find pharmaceuticals that partially replicate the changes induced by nutrient sensing regulators of metabolism, and thus improve health without eating less.
Any investigation of the mechanisms of calorie restriction and intermittent fasting is a complex business: a lower calorie intake produces sweeping changes in the behavior of cells and systems in the body, and metabolism is far from completely understood. The research community will only understand the fine details of exactly how eating less increases life span when they understand the fine details of cellular metabolism as a whole: how variations in metabolism determines variations in pace of aging. The achievement of that challenging goal lies decades in the future, which is one good reason not to bet on calorie restriction and fasting mimetic drugs to produce large gains in human life span any time soon.
The worldwide increase in life expectancy has not been paralleled by an equivalent increase in healthy aging. Developed and developing countries are facing social and economic challenges caused by disproportional increases in their elderly populations and the accompanying burden of chronic diseases. The primary goal of aging research is to improve the health of older persons and to design and test interventions that may prevent or delay age-related diseases. Although environmental quality and genetics are not under our direct control, energy intake is. Both hypo- and hypernutrition have the potential to increase the risk of chronic disease and premature death. Manipulation of a nutritionally balanced diet, whether by altering caloric intake or meal timing, can lead to a delay of the onset and progression of diseases and to a healthier and longer life in most organisms.
An emerging area of research is the investigation of the independent consequences of variations in meal size (through the control of energy intake) and meal frequency (by controlling the time of feeding and fasting) on the incidence or amelioration of multiple age-related diseases, including cardiovascular disease, diabetes, cancer, and dementia. These studies are starting to reveal that health-span and life-span extension can be achieved by interventions that do not require an overall reduction in caloric intake.
We discuss four experimental strategies aimed at altering energy intake or the duration of fasting and feeding periods that result in improved aspects of health in mammals. These are (i) classical caloric restriction, in which daily caloric intake is typically decreased by 15 to 40%; (ii) time-restricted feeding (TRF), which limits daily intake of food to a 4- to 12-hour window; (iii) intermittent or periodic full or partial fasting, that is a periodic, full- or multiday decrease in food intake; and (iv) fasting-mimicking diets (FMDs) that use a strategy to maintain a physiological fasting-like state by reducing caloric intake and modifying diet composition but not necessarily fasting. We also summarize the metabolic and cellular responses triggered by these feeding regimens and their impact on physiology, focusing on studies in rodents, monkeys, and humans.
Although the specific mechanisms are far from being fully understood, this periodic absence of energy intake appears to improve multiple risk factors and, in some cases, reverse disease progression in mice and humans. Thus, the time is ripe to add to our understanding of the molecular mechanisms of action and efficacy of these dietary interventions to the foundation for future clinical trials. We expect that these dietary interventions combined with classical pharmacology and clinical practice will yield interventions that will improve human health and enhance health span and quality of life as we grow old.
Another Study Demonstrating that Older People Fail to Exercise Sufficiently
Numerous studies demonstrate that increased exercise in the elderly reduces mortality risk and improves many measures of health. The glass half empty view of these results is that most people in wealthy, technological societies are not exercising sufficiently, and thus sabotaging their health. This conclusion is supported by the reduced presence of many of the characteristic aspects of age-related decline observed in hunter-gatherer populations, despite comparatively poor access to medical support throughout life. Exercise too little, and the result is that the decline into frailty is faster and greater than it might be. No-one can yet choose to avoid aging, as that will require rejuvenation biotechnologies, but it nonetheless still possible to choose poorly in life, in ways that will make aging notably worse.
The people participating in this research participated in a controlled, personalised programme of strength, balance, and walking exercises adapted to their possibilities, even during the acute phase of their diseases. Depending on the status of each patient, training intensity ranging between 30% and 60% of their muscular capacity was specified, so they did leg and arm exercises. These sessions lasted twenty minutes twice a day (morning and afternoon), over between five and seven consecutive days (including weekends and public holidays) under the individual supervision of experts in the field of physical exercise for the elderly.
The results of the study show that when discharged from hospital, the group that had participated in the prescribed programme of exercise achieved, in comparison with those who had not done it, a total of 2.2 points above the average on a maximum score of 12 in the SPPB (Short Physical Performance Battery) functional assessment tool, which measures balance, walking speed and leg strength, and 6.9 points above the average score in the Barthel Functional Index for Activities of Daily Living, which has a maximum score of 100 points. "Until now, no one had suggested that patients of this type (elderly people with a range of diseases) could benefit in just five days from a personalised exercise programme far removed from the usual message of 'get up and walk along the corridor a little' or 'rest in bed or in an armchair.´"
Significant benefits of the intervention from the cognitive and life quality perspective were also found. These improvements were achieved without any side effects or increase in hospital stay. "Nevertheless, this intervention did not change the rate of re-admittance or mortality three months later. In such an elderly population as those in the study and with a theoretically short life expectancy following hospitalisation, the aim of our intervention was not to increase the quantity but the quality of life. Sometimes we believe that improvements in technologies or the latest innovative treatment can provide all the solutions for our problems, but we are not aware that disability generated by hospitalisation may exert a greater impact than the very disease that prompted admittance in the first place. In this respect the hugely positive effect that physical exercise can have on disease prevention and treatment is reiterated."
Alzheimer's Subtypes Differentiated by How and Why Amyloid-β Accumulates
The authors of this open access commentary paint a picture of Alzheimer's disease as a condition that starts in a variety of different ways, all of which lead to amyloid-β accumulation, and this is then the common gateway to pathology and dementia. Once an individual begins to accumulate raised levels of amyloid-β, then the characteristic degeneration of Alzheimer's proceeds from there. This is a slow burn over years or decades in which the biochemistry of the brain becomes ever more aberrant, culminating in the development of tau aggregates, inflammation, dementia, and cell death.
The question has always been why only a fraction of people with any given risk factor go on to develop raised amyloid-β levels and full blown Alzheimer's disease. A variety of explanations are presently in various stages of construction and proof, most of which propose a way in which elevated amyloid-β levels might arise in only a portion of the population. Examples include persistent viral infection and differences in the drainage of cerebrospinal fluid through the cribriform plate.
Postmortem data clearly shows that Alzheimer's disease (AD) pathology rarely occurs in isolation. Most AD patients harbor more than one pathology in the brain, with cerebrovascular disease being the most common coexisting pathology. Furthermore, the frequency of both cerebrovascular and Alzheimer's disease increases with age. However, in what way cerebrovascular disease and AD pathology act in synergy leading to downstream neurodegeneration and dementia is still unknown.
Cerebral amyloid angiopathy (CAA), a form of cerebrovascular disease resulting from amyloid deposition in vessel walls, may be the link between these two frequently coexisting pathologies. It is interesting that anti-amyloid therapy has been reported to increase the incidence of microbleeds, potentially due to removal of amyloid through vessel walls. The big question is whether CAA is just a passenger on the AD train. How does CAA interact with amyloid and tau pathology? For instance, does CAA come in early on in disease pathogenesis by affecting the spread of neurofibrillary tangles across the brain? Or is CAA an event occurring in later stages, acting downstream to amyloid and tau pathology thus mostly contributing to neurodegeneration and brain atrophy? All these questions remain largely unanswered.
We recently conducted a comprehensive characterization of these AD subtypes in terms of cerebrovascular disease. We concluded that CAA seems to make a stronger contribution to hippocampal-sparing and minimal atrophy AD, whereas hypertensive arteriopathy, another form of cerebrovascular disease, may make a stronger contribution to typical and limbic-predominant AD. Evidence suggests that neurodegeneration can be expressed differently across different AD subtypes. Future research will also have to answer why amyloid pathology starts, what is triggering the cascade, and whether this differs in the different subtypes. Current data shows that dementia in AD is a downstream event that can be reached along different pathways. These different pathways may necessitate their own specific therapeutic strategies.
MRI Scans Predict Development of Dementia a Few Years in Advance
Researchers here demonstrate that MRI scans of white matter in the brain can be used to visualize a form of dysfunction that is strongly associated with the near term development of dementia in patients already showing some degree of cognitive decline. Given that low cost approaches to predicting the declines of neurodegeneration earlier rather than later are still thin on the ground, possibilities such as this one are valuable indeed. The earlier the determination that dementia is ahead, the more opportunities there are to enact preventative strategies.
Neurologists can get a ballpark estimate of a patient's risk of Alzheimer's dementia using the Mini-Mental State Examination questionnaire, or by testing for the high-risk form of the gene ApoE, which increases a person's risk of Alzheimer's by up to 12-fold. Both tests were about 70 to 80 percent accurate in this study. Other assessments, such as PET scans for plaques of Alzheimer's proteins in the brain, are good at detecting early signs of Alzheimer's disease, but available to few patients. PET scans are expensive and require radioactive materials not found in a typical hospital.
In a small study, researchers have shown that MRI brain scans predict with 89 percent accuracy who would go on to develop dementia within three years. MRI brain scans are widely available and give doctors a glimpse into what's going on inside a person's brain. The researchers used a technique called diffusion tensor imaging to assess the health of the brain's white matter, which encompasses the cables that enable different parts of the brain to talk to one another. Diffusion tensor imaging is a way of measuring the movement of water molecules along white matter tracts. If water molecules are not moving normally it suggests damage to white tracts that can underlie problems with cognition.
Researchers identified 10 people whose cognitive skills declined over a two-year period and matched them by age and sex with 10 people whose thinking skills held steady. The average age of people in both groups was 73. Then, the researchers analyzed diffusion tensor MRI scans taken just before the two-year period for all 20 people. The researchers found that people who went on to experience cognitive decline had significantly more signs of damage to their white matter. The researchers repeated their analysis in a separate sample of 61 people, using a more refined measure of white matter integrity. With this new analysis, they were able to predict cognitive decline with 89 percent accuracy when looking at the whole brain. When the researchers focused on specific parts of the brain most likely to show damage, the accuracy rose to 95 percent.
A DNA Vaccine Reduces Both Amyloid-β and Tau Aggregates in Mice
Alzheimer's disease begins with increasing amounts of amyloid-β in the brain, leading to solid aggregates that distort cell function and cause a comparatively mild level of cognitive impairment. Over time, this initial abnormal biochemistry sets the stage for the later, much more serious accumulation of an altered form of tau protein. Tau aggregates causes severe loss of function and cell death, with dementia as the result. The research community is divided over the deeper origins of Alzheimer's, the processes that cause only some people to exhibit raised levels of amyloid-β, but it seems clear that comprehensive, effective treatment strategies must in some way tackle both amyloid and tau aggregates. If one therapy can clear out both forms of aggregate, then all to the good, but unfortunately there are few examples capable of this outcome.
In the case here, the reduction in amyloid-β is achieved directly, while the reduction in tau is achieved indirectly. The particular form of amyloid-β targeted by the therapy is involved in altering tau in ways that encourage its aggregation. Whether this mechanism is important in humans to the same degree that it is important in the particular animal model used here is a question best resolved by moving to human trials. One of the challenges inherent in Alzheimer's disease research is that humans are one of the only species to exhibit anything even remotely resembling the condition. Thus the mice used for testing are altered in highly artificial ways to produce models of Alzheimer's. The fine details of how the models differ from human Alzheimer's biochemistry are of great importance, and one of the reasons for the lengthy catalog of failure in clinical trials over the past few decades.
A DNA vaccine tested in mice reduces accumulation of both types of toxic proteins associated with Alzheimer's disease. The vaccine is delivered to the skin, prompting an immune response that reduces buildup of harmful tau and beta-amyloid - without triggering severe brain swelling that earlier antibody treatments caused in some patients. "This study is the culmination of a decade of research that has repeatedly demonstrated that this vaccine can effectively and safely target in animal models what we think may cause Alzheimer's disease. I believe we're getting close to testing this therapy in people."
Although earlier research established that antibodies significantly reduce amyloid buildup in the brain, researchers needed to find a safe way to introduce them into the body. A vaccine developed elsewhere showed promise in the early 2000s, but when tested in humans, it caused brain swelling in some patients. The new idea was to start with DNA coding for amyloid and inject it into the skin rather than the muscle to produce a different kind of immune response. The injected skin cells make a three-molecule chain of beta-amyloid (Aβ42), and the body responds by producing antibodies that inhibit the buildup of amyloid and indirectly also of tau.
The latest study - consisting of four cohorts of between 15 and 24 mice each - shows the vaccine prompted a 40 percent reduction in beta-amyloid and up to a 50 percent reduction in tau, with no adverse immune response. If amyloid and tau are indeed the cause of Alzheimer's disease, achieving these reductions in humans could have major therapeutic value. The study is the latest contribution to decades of research focusing on clearing toxic proteins in hopes of preventing or slowing the progression of Alzheimer's disease.
Bioengineered Intervertebral Discs are Implanted Successfully in Goats
Significant progress has been made in the tissue engineering of intervertebral discs in recent years. Researchers here report on an initial study in larger animals, demonstrating that the implanted intervertebral discs exhibit the correct behavior and otherwise hold up well for at least a few months. Degeneration of intervertebral discs is universal to at least some degree in older people, with a sizable portion of the population suffering pain and loss of function, and the consequences of disc injury at any stage of life can also be lasting and severe. Thus approaches that can meaningfully address this issue are most welcome, whether they involve engineered replacement discs, or act through forms of regenerative therapy that can spur existing tissues to restore themselves.
The soft tissues in the spinal column, the intervertebral discs, are essential for the motions of daily life, such as turning your head to tying your shoes. At any given time, however, about half the adult population in the United States is suffering from back or neck pain, for which treatment and care place a significant economic burden on society - an estimated 195 billion a year. While spinal disc degeneration is often associated with that pain, the underlying causes of disc degeneration remain less understood. Today's approaches, which include spinal fusion surgery and mechanical replacement devices, provide symptomatic relief, but they do not restore native disc structure, function, and range of motion, and they often have limited long-term efficacy. Thus, there is a need for new therapies.
Tissue engineering holds great promise. It involves combining the patients' or animals' own stem cells with biomaterial scaffolds in the lab to generate a composite structure that is then implanted into the spine to act as a replacement disc. For the last 15 years, a team has been developing a tissue engineered replacement disc, moving from in vitro basic science endeavors to small animal models to larger animal models with an eye towards human trials. Past studies from the team successfully demonstrated the integration of their engineered discs, known as disc-like angle ply structures (DAPS), in rat tails for five weeks. This latest research extended that time period in the rat model - up to 20 weeks - but with revamped engineered discs, known as endplate-modified DAPS, or eDAPS, to mimic the structure of the native spinal segment. The addition of the endplates helped to retain the composition of the engineered structure and promote its integration into the native tissue.
MRI, along with histological, mechanical, and biochemical analyses, showed that the eDAPS restored native disc structure, biology, and mechanical function in the rat model. Building off that success, the researchers then implanted the eDAPS into the cervical spine of goats. They chose the goat because its cervical spinal disc dimensions are similar to humans' and goats have the benefit of semi-upright stature. Researchers demonstrated successful total disc replacement in the goat cervical spine. After four weeks, matrix distribution was either retained or improved within the large-scale eDAPS. MRI results also suggest that disc composition at eight weeks was maintained or improved, and that the mechanical properties either matched or exceeded those of the native goat cervical disc.
Atrophy of the Thymus Accelerates the Progression of Atherosclerosis
The thymus is where T cells mature, the training ground for the footsoldiers of the adaptive immune system. As the thymus declines in size and function with age, the supply of new T cells falls. This constrains and distorts the existing population of T cells, resulting eventually in chronic inflammation and immunosenescence, the failure the immune response and resulting vulnerability to pathogens and cancer. Atherosclerosis, meanwhile, is a condition of the innate immune system, in that it is caused by macrophages - a type of innate immune cell with origins that have nothing to do with the thymus - flocking to try and fail to remove deposits of cholesterol from blood vessel walls. The resultant dysfunction and death of those macrophages generates growing plaques of fat and cell debris that narrow and weaken blood vessels.
Given these two quite separate sets of mechanisms, what is the link between the two? The answer is chronic inflammation. The processes of atherosclerosis respond strongly to inflammation, as inflammatory signaling changes the behavior of macrophages for the worse. Badly behaving macrophages do less to clean up cholesterol in blood vessel walls, and may even actively make the situation worse by propagating inflammatory signals themselves. That much is straightforward and well-explored by the research community. The novel speculation in the open access paper here is a link between low-density lipoprotein and decline in thymic function, making a feedback loop of sorts. This is the first time I've seen that put forward as a hypothesis, and I have no idea as to its plausibility.
Atherosclerosis is a complex disease characterized by smooth muscle cell proliferation, cholesterol deposition, and the infiltration of mononuclear cells. The formation and progression of atherosclerotic plaques result in the disruption of organ perfusion, causing cardiovascular and cerebrovascular diseases. It has been proved that immune responses participate in every phase of atherosclerosis. There is increasing evidence show that both adaptive and innate immunity tightly regulate the development and progression of atherosclerosis.
Atherosclerosis is considered as an immune inflammatory disease, and the T cell-mediated immune inflammatory response plays an important role in the pathogenesis of atherosclerosis. T cells mature in the thymus and are involved in the process of atherosclerosis induced by inflammation and immune response. Inflammatory mechanisms and immune system mechanisms are crucially involved in the pathophysiology of atherosclerosis and cardiovascular disease. T lymphocytes are involved and play an important role in both the inflammatory response and the immune response. An imbalance of the degree of activation of the protective Treg lymphocytes, the pro-inflammatory and cytotoxic macrophages and T-effector lymphocytes could thus be at the origin of the triggering or not of progression of vascular injury. However, all of these processes are closely associated with thymus function. In other words, changes in the function of thymus will be deeply affecting the process.
Based on previous research, we can speculate that the changes of thymus function may have an impact on the process of atherosclerosis. The mechanism of thymus involvement in the process of atherosclerosis is assumed as follows: Low density lipoprotein or cholesterol reduces the expression of the thymus transcription factor Foxn1 via low density lipoprotein receptors (LDLR) on the membrane surface and low density lipoprotein receptor-related proteins on the cell surface, which cause the thymus function decline or degradation. The imbalance of T cell subgroups and the decrease of naive T cells due to thymus dysfunction cause the increase or decrease in the secretion of various inflammatory factors, which in turn aggravates or inhibits atherosclerosis progression and cardiovascular events. NK T cell, dendritic cells, and macrophages can affect the process of atherosclerosis by affecting the production of naive T cells through the thymus. Furthermore, these cells can also participate in the progression of atherosclerosis via the direct secretion of cytokines or inducing other cells to secrete cytokines.
According to our hypothesis, various biotechnologies can be selected to improve aging thymus function in animal experiments. In the clinical treatment of atherosclerosis, and even other immune-related diseases, we may consider improving the expression of foxn1 in the human body, thereby improving or restoring aging thymus function and resisting the related-diseases caused by the decline of immunity. Further investigation on changes of thymus function will help to develop new therapeutic targets that may improve outcomes in atherosclerosis and cardiovascular disease and discover novel approaches in the treatment of atherosclerosis and vascular disease.