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- Continued Exploration of the Mechanisms of Cellular Senescence
- What to Learn from the Debate over Adult Human Neurogenesis?
- GrimAge is the Latest Evolution of the Epigenetic Clock
- The Goal of Symbiotic Microbes in Tissues, Generating Additional Oxygen as Required
- It Doesn't Matter How Fit You Are, Excess Fat Tissue Still Raises the Risk of Cardiovascular Disease
- The Epigenetic Clock Does Not Reflect Long-Term Physical Activity Differences in Twins
- The Acceleration Years in the Development of Rejuvenation Therapies
- An Approach to In Vivo Detection of Senescent Cells
- Poor Sleep Causes Raised Levels of Tau in the Brain
- CXCL12 Promotes Small Artery Growth in Injured Hearts, but Why Not Apply this Approach in Advance of Injury as Well?
- The Importance of Macrophages in Kidney Regeneration
- Hypertension May Accelerate Neurodegeneration by Reducing Clearance of Metabolic Waste via Cerebrospinal Fluid Drainage
- The Interactions of Frailty, Exercise, and Risk of Dementia
- Aerobic Exercise Reduces Cancer Incidence and Age-Related Inflammation in Mice
- Reduced Blood Pressure Lowers Risk of Mild Cognitive Impairment, but Not Dementia?
Continued Exploration of the Mechanisms of Cellular Senescence
Today, a pair of papers that are representative of present interest in the deeper mechanisms of cellular senescence. Senescent cells have of late become a major focus in the aging research community, now that scientists are largely convinced that (a) accumulation of these cells is a significant cause of aging, and (b) removing them can reverse aging and age-related disease to a large enough degree to justify significant investment in further development. Better late than never! The evidence has been compelling for decades, but only in 2011 was sufficient funding raised by a sufficiently well-regard research group to build an animal study of senescent cell clearance that the rest of the scientific community found compelling. This could all have happened ten or twenty years earlier, given different people in charge of budgets and strategies.
Still, here we are now. There is presently something of a gold rush underway in the research and development communities when it comes to the biochemistry of cellular senescence. Even setting aside more direct approaches such as suicide gene therapies or immunotherapies capable of targeting senescent cells for destruction, researchers have discovered at least four plausible mechanisms and associated drug candidates that can intervene in the peculiar biochemistry of these cells in order to nudge them into apoptosis and self-destruction. Companies have been founded to develop small molecule drugs based on a couple of these mechanisms, and hundreds of millions in funding has been raised for clinical development. There is the sense that any similar new discovery will open the same sort of doors for its discoverers, and the expectation that many more useful mechanisms will be discovered.
Destruction of senescent cells is not the only goal in the research community. Other groups are more interested in preventing senescence from taking place, or in trying to modulate the harmful inflammatory signaling that allows a small number of senescent cells to cause widespread disruption of tissue function. I think that both of these are inferior approaches, because senescence is a mark of damage and why keep damaged cells around on the one hand, and on the other safely altering this poorly understood and diverse cell signaling is a vast, enormously complex project. Nonetheless, there will still be funding readily available for those groups that make discoveries in this field, at least until a few attempts at producing clinical therapies along these lines fail to do as well as the more direct approach of just destroying these unwanted cells. That is the way I expect matters to progress, in any case.
S100A13 promotes senescence-associated secretory phenotype and cellular senescence via modulation of non-classical secretion of IL-1α
Senescent cells display the senescence-associated secretory phenotype (SASP) which plays important roles in cancer, aging, etc. Cell surface-bound IL-1α is a crucial SASP factor and acts as an upstream regulator to induce NF-κB activity and subsequent SASP genes transcription. IL-1α exports to cell surface via S100A13 protein-dependent non-classical secretory pathway. However, the status of this secretory pathway during cellular senescence and its role in cellular senescence remain unknown.
Here, we show that S100A13 is upregulated in various types of cellular senescence. S100A13 overexpression increases cell surface-associated IL-1α level, NF-κB activity, and subsequent multiple SASP genes induction, whereas S100A13 knockdown has an opposite role. We also exhibit that Cu2+ level is elevated during cellular senescence. Lowering Cu2+ level decreases cell surface-bound IL-1α level, NF-κB activity, and SASP production. Further, impairment of the non-classical secretory pathway of IL-1α delays cellular senescence.
D-amino Acid Oxidase Promotes Cellular Senescence via the Production of Reactive Oxygen Species
d-amino acid oxidase (DAO) is a flavin adenine dinucleotide (FAD)-dependent oxidase metabolizing neutral and polar d-amino acids. Unlike l-amino acids, the amounts of d-amino acids in mammalian tissues are extremely low, and therefore, little has been investigated regarding the physiological role of DAO. We have recently identified DAO to be upregulated in cellular senescence, a permanent cell cycle arrest induced by various stresses, such as persistent DNA damage and oxidative stress. Because DAO produces reactive oxygen species (ROS) as byproducts of substrate oxidation and the accumulation of ROS mediates the senescence induction, we explored the relationship between DAO and senescence.
The accumulation of ROS is widely observed in senescence induced by various types of stress. ROS can hasten senescence through induction of oxidative DNA damage, and a recent study has shown that a positive feedback loop between ROS production and DNA damage response establishes senescence with the contribution of p21. Although ROS are reported to mediate p53-dependent cell cycle arrest, the mechanism by which p53 regulates ROS production in the process of senescence induction remains mostly unclear. We have recently identified DAO to be up-regulated specifically in senescent cells and shown the direct transcriptional regulation of DAO by p53.
In the present study, we evaluated the functional association of DAO with the senescence process. We revealed that DAO accelerates senescence via enzymatic generation of ROS and that d-arginine, a substrate for DAO, is abundantly present in cultured cancer cells. DAO is activated in response to DNA damage presumably due to an increase in availability of its coenzyme, FAD.
What to Learn from the Debate over Adult Human Neurogenesis?
Neurogenesis is the name given to the processes by which new neurons are created and integrated into neural circuits. More neurogenesis is generally agreed to be beneficial, in the same way as stem cell activity in other tissues is beneficial, by helping to maintain tissue function in the face of injury and biological wear and tear. As is the case for stem cell function in general, neurogenesis falters with age where it is known to occur throughout life. Beyond this point of maintenance, a process common to all tissues, there is also the matter of cognitive function to consider, however. Greater neurogenesis may aid in learning, memory, and other capabilities, distinctly from the role it plays in normal tissue maintenance.
Neurogenesis obviously occurs throughout the brain in early life, as this organ is constructed and finalized. Until the 1990s it was thought that this process ceased in most areas of the brain in adults. Then it was proven that adult neurogenesis does in fact occur in mice, in areas of the brain important to memory and cognition, which was at the time quite the upheaval. Since then near all of the research on this topic has taken place in mice, as it is very challenging to investigate human brain tissue. Nonetheless, the consensus has been that the lessons learned in mice also apply to humans. As a consequence, the goal of artificially increased neurogenesis in older people drives many medical research programs. Scientists seek the foundations for therapies that can slow cognitive decline or produce greater recovery following brain injury, and hope that this can be achieved by adjusting levels of regulatory proteins controlling neurogenesis.
Another upheaval in the matter of adult neurogenesis is underway. This past year has seen a vigorous debate over whether or not the findings in mice do apply to humans. This started with a careful study that found no evidence of adult neurogenesis in our species. It was shortly followed by another careful study that did show evidence of adult neurogenesis. A great deal of commentary on all sides followed these findings. Today's paper is an example of the type, in this case siding with the uncomfortable position that perhaps neither older mice nor humans exhibit meaningful neurogenesis. If this case, this may complicate and delay the advent of any therapies based on spurring neurogenesis in the aged brain.
Lessons learned from the adult neurogenesis debate
Since the 1960s, consensus about whether human adults generate new neurons with age has swayed back and forth from "yes, at least in some places in the brain" to "no, not at all." The debate reignited in 2018 when two headline-grabbing papers, published weeks apart, made convincing arguments for each side. "It's clear that there is a lot of controversy, which to me seems unwarranted because a yes or no for 'is there adult neurogenesis' is a little too simplistic and distracts us from other important questions. It's worth asking if methodological differences are the only reason that some people aren't finding new neurons or if there is some truth to the observations that neurogenesis may be limited with age in humans. I wanted to take a quantitative look at the research and see where it all leads."
One stand-out issue is that labs that find more neurogenesis in mice than in humans are studying it in young mice, while human research is often conducted in adults from middle to old age. In addition, primates and rodents develop most of their neurons at different times in their early development: human neuron populations peak during the first half of gestation, while mouse neurogenesis continues through birth or after birth. So the observation that there is more neurogenesis in mice might also be because the rodent brain develops later in life. "The literature also indicates that if you look at a middle-aged rodent, it doesn't have much neurogenesis either. If we were to study the same in relative-aged human subjects, I don't think the story is much different. For much of the adult lifespan, we're not bursting at the seams with new neurons. While that may be disconcerting for people, it does reconcile the field: it's not that some studies are right and some are wrong."
Recalibrating the Relevance of Adult Neurogenesis
Reports of limited neurogenesis in adult humans have been difficult to reconcile with animal work demonstrating persistent neurogenesis throughout life, and with human studies arguing for lifelong neurogenesis. Our review suggests that, once developmental timing is accounted for, the human and animal literatures are generally consistent with one another: the human hippocampus develops largely prenatally, leaving less opportunity for postnatal neurogenesis. In contrast, the rodent dentate gyrus forms postnatally and is typically studied in adolescence and young adulthood, when neurogenesis rates remain high. Thus, some confusion has arisen as a result of modeling adult humans with juvenile rodents. While it remains unresolved whether neurogenesis drops to zero in adult humans, our comparative analysis suggests that it falls to low rates for much of adult life in all species.
What then is the relevance of adult neurogenesis for humans? First, low rates of neurogenesis in adulthood, over years and decades, may have substantial additive effects that promote long-term health. Second, higher rates in early life may play a significant role in childhood and adolescent brain function, when many mental health disorders originate. Uncertainties about human-animal differences, and the extent to which cellular properties reflect maturational states versus persistent features, also highlight opportunities for future research. In summary, consideration of the broader neurodevelopmental context will help us take advantage of the benefits that neurogenesis may offer for human mental health.
GrimAge is the Latest Evolution of the Epigenetic Clock
The original epigenetic clock is a measure of age, a weighted algorithmic combination of specific DNA methylation sites on the genome. Numerous variations on this theme are being produced, and here I'll point out news on the latest, a metric called GrimAge. DNA methylation is an epigenetic mechanism that steers protein production and thus cell behavior. Epigenetic clocks correlate well with chronological age, and it has been shown that populations of older individuals with pronounced age-related disease or otherwise exhibiting higher mortality rates tend to have higher epigenetic ages.
There are some problematic exceptions, groups expected to show higher epigenetic age, but who do not, but researchers are nonetheless forging ahead to try to turn this tool into a robust method of assessing the burden of cell and tissue damage that causes aging. If one or more clock variants can be made robust enough, the variations understood and linked to specific causes and dysfunctions of aging, then these epigenetic clocks offer the possibility of greatly accelerating the development of rejuvenation therapies.
At present the only robust way of demonstrating that a therapy does in fact turn back aging, and measuring the degree to which it does so, is to run life span studies. When using mice, this is a greater expense in time and funds than most research groups can stomach, and carrying out such studies in humans is just out of the question. What is needed is a way to quickly assess how greatly a therapy reduces the burden of aging, a test that can be applied beforehand, and a month or two after treatment, and the result compared. Even as a way to cull the useless and marginal work in the field of human aging, work that consumes far too much attention and funding, this would be very valuable. More importantly, it would allow researchers to more cost-effectively assess scores of promising approaches that are presently lacking in the funds and support to prove their worth.
The epigenetic clock: a molecular crystal ball for human aging?
A hat trick of new epigenetic clocks has recently been published: The Skin and Blood clock provides a more precise estimation of chronological age in tissues and cell types frequently used in research and forensics, while PhenoAge and GrimAge aim to capture biological aging and derive an improved prediction of mortality and morbidity risks. Together, these new epigenetic clocks present valuable tools to investigate human aging, shed light on the question of why we all age differently, and develop strategies to extend human lifespan and healthspan.
Horvath's multi-tissue clock is based on DNA methylation data. DNA methylation, the addition of methyl groups to cytosine bases of the DNA, is the most widely studied epigenetic modification so far. It plays an important role in the regulation of gene expression, altering the phenotype without changing the genotype. A particular locus in the genome can either be methylated or unmethylated. But as DNA methylation measurements are usually obtained from a pool of tens of thousands of cells, what is measured is the proportion of the cells in which a locus is methylated. In many positions of the human genome, this methylation heterogeneity changes with age. These usually small but consistent age-associated changes in DNA methylation are what make the epigenetic clock work. And it works very precisely, with a median absolute error (MAE) of only 3.6 years, clearly outperforming previously used molecular biomarkers of age.
DNA methylation GrimAge strongly predicts lifespan and healthspan
DNA methylation (DNAm) levels have been used to build accurate composite biomarkers of chronological age. DNAm-based age (epigenetic age) estimators predict lifespan after adjusting for chronological age and other risk factors. Moreover, they are also associated with a large host of age-related conditions. Recently, DNAm-based biomarkers for lifespan (time-to-death due to all-cause mortality) have been developed.
Many analytical strategies are available for developing lifespan predictors from DNAm data. The single stage approach involves the direct regression of time-to-death (due to all-cause mortality) on DNAm levels. By contrast, the current study employed a novel two-stage procedure: In stage 1, we defined DNAm-based surrogate biomarkers of smoking pack-years and a selection of plasma proteins that have previously been associated with mortality or morbidity. In stage 2, we regressed time-to-death on these DNAm-based surrogate biomarkers. The resulting mortality risk estimate of the regression model is then linearly transformed into an age estimate (in units of years). We coin this DNAm-based biomarker of mortality "DNAm GrimAge" because high values are grim news, with regards to mortality/morbidity risk.
Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death, time-to-coronary heart disease, time-to-cancer, its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause. Adjusting DNAm GrimAge for chronological age generated novel measure of epigenetic age acceleration, AgeAccelGrim. AgeAccelGrim is strongly associated with a host of age-related conditions including comorbidity count. Overall, these epigenetic biomarkers are expected to find many applications including human anti-aging studies.
The Goal of Symbiotic Microbes in Tissues, Generating Additional Oxygen as Required
We live in an era of biotechnology, of tremendous year by year increases in the capacity to engineer the fundamental mechanisms of life and disease. The research community and funding institutions should aim high, aim at the new and the amazing, rather than slouching forward in the service of crafting yet more marginal, incremental improvements to existing forms of therapy. Sadly, mediocrity rules when it comes to all too much of the research community. Vision is lacking, and far too few people are willing to tread the roads yet untraveled.
Why is it necessary to spend so much time and effort to convince people to fund and work on rejuvenation therapies after the SENS model, based on the repair of cell and tissue damage? Because this strategy is comparatively new, because it is different from the largely futile efforts to paper over age-related diseases that have gone before. We humans are conservative, and favor existing strategies, even when they are poor, even when new directions are highly promising. Beyond the matter of rejuvenation, there are a thousand plausible new directions in medicine and biotechnology that are given little attention for all the same reasons, whether the DRACO approach to defeating viruses, or the topic of today's paper, the introduction of symbiotic bacteria capable of generating oxygen to supply ischemic tissues.
The researchers here focus on treatment of ischemia following heart attack or stroke, and on largely unmodified symbiotic organisms that might be used for this purpose. This is but a single step upon a long road of possibilities. Why not an enhancement biotechnology for healthy people, in which symbiotic bacteria dwell in the body, ready to provide oxygen on demand? A gene therapy to add a wholly artificial gene to human cells, one connected to a promoter that triggers only in hypoxic conditions, with the result that it supplies a protein that engineered symbiotic microorganisms consume as fuel for their oxygen-production engines. This sort of machinery could be described in some detail today, then built with today's technology, tested in animals, and delivered into human tissues with the robust gene therapy platforms that will emerge over the next decade. The result will people resilient to drowning, people with incredible endurance, people who can survive heart attacks, strokes, and other forms of blood vessel injury with little additional damage.
This will not happen any time soon, but not because it is technically infeasible. It will not happen because there is little overlap in this world between those with ambition on the one hand, and those with funding and power on the other. In this age of rapid, radical progress in biotechnology, there is all too little will to reach for the myriad possibilities offered.
Photosynthetic symbiotic therapy
Engineered O2-producing biomaterials represent an emerging field with enormous potential to address tissue ischemia and hypoxia without revascularization. The clinical applications span nearly the entire domain of medicine and include the areas of tissue engineering and regeneration, organ preservation, wound healing, diabetic microvascular disease, and cardiovascular, cerebrovascular, and peripheral vascular disease. Nature, however, evolved the most elegant O2-producing biomaterial 3.5 billion years ago in the form of photosynthetic cyanobacteria, which are responsible for the relative abundance of O2 in Earth's atmosphere today. These ancestors of the chloroplast convert CO2 and water into O2 and glucose using light as an energy source. Recently, teams have begun to engineer symbioses between cyanobacteria or other photoautotrophic algae and heterotrophic cells such as those of mammals. In this relationship, the photosynthetic microorganism recycles CO2 produced by heterotrophic cellular respiration and generates O2 that helps sustain the heterotrophic partner.
The first use of a photosynthetic microorganism to remedy tissue hypoxia in vivo was reported in 2012. By placing a gas-permeable pouch containing a light-emitting diode and the photosynthetic microalga Chlorella vulgaris in the perfluorocarbon-filled peritoneal cavity of hypoventilated rats, the team demonstrated that Chlorella could supplement gas exchange in rats with respiratory insufficiency. The researchers also explored the use of photosynthetic symbiosis to enhance the viability of heterotopically-transplanted rat pancreases harvested 3 hours after cardiac death. The team demonstrated that a majority of diabetic recipient rats receiving pancreases stored in traditional cold preservation solution for 30 minutes exhibited severe glucose dysregulation and died within 5 hours after surgery. All rats receiving pancreases stored similarly but with Chlorella in gas-permeable bags at mild hypothermia (22°C), however, had normal blood glucose levels and survived beyond 1 week after surgery.
Direct inoculation of host tissues with microorganisms in solution risks rapid loss of the symbiotic microbes. Although no in vivo study has yet to demonstrate a significant immune response against a photosynthetic symbiont (i.e. against S. elongatus or C. reinhardtii in zebrafish, mouse, or rat models), delivery via a bioengineered construct nevertheless reduces the rate of cell dispersal. To this end, researchers have conducted impressive pioneering work on the development of photosynthetic algae-seeded scaffolds. Using an FDA-approved collagen-based scaffold, the team demonstrated that C. reinhardtii seeded within the scaffold were able to photosynthesize effectively and even proliferate. Moreover, C. reinhardtii co-cultured with murine fibroblasts within the scaffold were able to supply the fibroblasts with O2 in hypoxic conditions.
Thus far, photosynthetic symbiotic therapies have not taken full advantage of the immense genetic adaptability of cyanobacteria and microalgae. While researchers engineered C. reinhardtii to express and secrete vascular endothelial growth factor (VEGF), resulting in O2 delivery as well as neoangiogenesis when delivered into zebrafish and rat tissues in vivo, nearly all attempts to treat tissue ischemia or hypoxia using photosynthetic symbiosis have focused solely on gas exchange alone. Future studies should aim to expand the arsenal of clinically useful compounds produced by the photosynthetic symbiont and thereby augment its therapeutic potential. Overall, photosynthetic symbiosis represents a valuable untapped strategy for the development of novel engineered O2-generating biomaterials.
It Doesn't Matter How Fit You Are, Excess Fat Tissue Still Raises the Risk of Cardiovascular Disease
Being physically fit is very much better for long term health than being unfit. But in this era of cheap and attractive calories, it is quite possible to be both physically fit and overweight to some degree. Many people are. Unfortunately, being fit doesn't meaningfully protect against the detrimental effects of excess fat tissue on health and disease risk. If you are carrying more visceral fat tissue, then you have a higher risk of all of the common age-related diseases, when compared with someone of the same level of fitness with less visceral fat tissue.
Not so many years ago, metrics based on the ratio of height to waist circumference - such as the simple waist-stature ratio - began to appear in epidemiological studies as a replacement for the time-worn use of body mass index. The waist-stature ratio correlates more closely than body mass index with risk of disease, mortality, and other unfortunate aspects of aging. This points to the importance of visceral fat in disease processes. Even so it will take some time to percolate through the research community. Epidemiology doesn't move rapidly, and older data sets often lack the necessary information for use of waist-stature ratio, while most include body mass index.
How does visceral fat cause harm over the long term? Chronic inflammation is likely the primary mediating mechanism. Visceral fat cells are metabolically active, and when present in large numbers secrete signals that rouse the immune system. In addition, excess visceral fat appears to generate senescent cells at an accelerated rate, and these also secrete a mix of molecules that cause chronic inflammation. Fat cell debris further contains DNA fragments that aggravate the immune system in a different way. The inflammation generated by fat tissue disrupts processes of regeneration, and accelerates the progression of age-related diseases such as atherosclerosis and dementia.
Waist-stature ratio can indicate the risk of cardiovascular disease even in healthy men
Researchers have found that physically active men who were not overweight but whose waist-stature ratio (WSR) was close to the risk threshold were also more likely to develop heart disorders than individuals with lower WSRs. Recent research suggests that the WSR (waist circumference divided by height) is a more accurate predictor of cardiovascular risk than the body mass index (BMI), a widely used measure of body fat.
The researchers further investigated this hypothesis by analyzing the autonomic recovery of heart rate after aerobic exercise in healthy men with different WSRs. To this end, 52 physically active healthy men aged 18-30 were divided into the following three groups according to WSR: between 0.40 and 0.449, which is below the risk threshold for cardiovascular disease; between 0.45 and 0.50, which is close to the threshold; and between 0.50 and 0.56, which is above the threshold. The participants were tested on two separate days with a 48-hour interval between the two tests. Their heart rate and heart rate variability were measured while at rest and six times during a recovery hour to assess their speed of autonomic recovery after physical activity.
Analysis of the measurements showed that the autonomic recovery was slower in the groups with WSRs close to and above the risk threshold for heart disease after both the maximum effort test and moderate aerobic exercise. "We found that volunteers in the group with WSRs close to the risk limit were also more likely to develop cardiovascular disorders." The results of the statistical analyses suggested that two factors were most significantly correlated during the first ten minutes of the postexercise recovery period, when the parasympathetic nervous system (PNS) was being reactivated. Among other functions, the PNS, one of the three divisions of the autonomic nervous system, slows heart rate, and reduces blood pressure via the release of hormones.
Waist-Stature Ratio And Its Relationship With Autonomic Recovery From Aerobic Exercise In Healthy Men
Amongst the indicators of abdominal obesity, body mass index (BMI), waist circumference (WC), hip circumference (HC), conicity index (CI), waist-stature ratio (WSR) have been studied and are widely accepted in disease assessment, management and predictions in clinical practice and public health surveillance. Lately, WSR has been widely applied as it is simple, easy to measure and calculate. It is obtained by dividing the WC by height, in which WC demonstrates abdominal obesity and height remains constant in adults, which allows the possibility for direct comparisons in the general population.
Although the research literature has focused on obese patients with increased risk based on the WSR, it lacks evidence in subjects with values closer to the limit, herein moderate risk. In this sense, we appraised autonomic recovery after aerobic exercise in healthy men with different ranges of WSR. We found that healthy men with higher WSR accomplished delayed autonomic recovery following maximal effort exercise. Our results draw attention to the importance of cardiovascular prevention in the population within WSR values above 0.45, since we established that physically active men in this group offered slower autonomic recovery following aerobic exercise.
The Epigenetic Clock Does Not Reflect Long-Term Physical Activity Differences in Twins
Epigenetic clocks are a weighted algorithmic combination of specific DNA methylation markers, those that exhibit characteristic changes with age. The various iterations of the clock have a strong association with chronological age, and appear to reflect biological age as well, in that people with more pronounced age-related disease and populations with higher mortality rates tend to have a higher epigenetic age than their healthier peers. Since the clock was reverse engineered by analysis of DNA methylation and age data, there remains the question of what exactly it is measuring. There is no comprehensive map to definitively link changes in epigenetic markers with the progression of the causes of aging.
Thus it is presently hard for researchers to make good use of the clock in speeding up the development of potential rejuvenation therapies; given a result, there will be uncertainty over what the result means. Numerous studies have been carried out on the epigenetic clock and specific medical conditions and therapies. Some of the results are troubling, such as the one here. If one can take twins who have a lifetime of very different exercise habits behind them, and find that they have roughly the same epigenetic age, that is a challenge. The epidemiological and animal data on exercise, even the modest levels of physical activity discussed here, strongly indicates that it has a robust, measurable effect on mortality rate and risk of age-related disease. If that doesn't show up in the epigenetic clock, we must come back once again to ask just what is it that the clock measures.
Advances in the fields of molecular biology have produced novel promising candidate biomarkers and their combinations that may be considered as biological aging clocks. So far, one of the most promising new aging clocks is DNA methylation (DNAm) age, also known as the "epigenetic clock". DNAm age is a multi-tissue age estimate based on DNA methylation at 353 specific age-related CpG sites. It is determined with a special algorithm, which is publicly available. The epigenetic clock appears to be associated with a wide spectrum of aging outcomes, most consistently mortality. Discrepancy between DNAm age and chronological age, i.e., higher "age acceleration" predicts all-cause mortality.
So far, it is also not clear whether the genetic component in variation of DNAm age changes over a life span. On the other hand, some environmental exposures and behaviors such as infections, diet, alcohol use, smoking, and work exposures predispose to age-related diseases and increase probability of death. Only part of individual variation to life expectancy can be accounted for using known and measured characteristics and exposure. An epigenetic clock could provide insights into the mechanisms behind why some individuals age faster than others and are more prone to age-related diseases and accelerated decline in physical function.
Physical activity is a potentially modifiable behavior that could slow down the rate of cellular and molecular damage accumulation and blunt the decline in physiological function with increasing age. The purpose of the study was to estimate the magnitude of genetic and environmental factors affecting variation in DNAm-based age acceleration in young and older monozygotic (MZ) and dizygotic (DZ) twins with a focus on leisure time physical activity.
The relative contribution of non-shared environmental factors was larger among older compared with younger twin pairs [47% versus 26%]. Correspondingly, genetic variation accounted for less of the variance in older compared with younger pairs [53% versus 74%]. We tested the hypothesis that leisure time physical activity is one of the non-shared environmental factors that affect epigenetic aging. A co-twin control analysis with older same-sex twin pairs (seven MZ and nine DZ pairs, mean age 60.4 years) who had persistent discordance in physical activity for 32 years according to reported/interviewed physical-activity data showed no differences among active and inactive co-twins, DNAm age being 60.7 vs. 61.8 years, respectively. Results from the younger cohort of twins supported findings that leisure time physical activity is not associated with DNAm age acceleration.
The Acceleration Years in the Development of Rejuvenation Therapies
The upward curve of technological progress is steepening, and this is particularly the case for the development of medical biotechnologies capable of meaningfully addressing the causes of aging. These are the acceleration years, in which the first rejuvenation therapies exist in prototype form, commercial development begins in earnest, and funding starts to pour into the field. That in turn drives funding into many neighboring areas of fundamental research that have previously struggled, bringing further rejuvenation therapies closer to viability. If you look at the outset of past fields of human scientific endeavor, most are stories of decades, sometimes generations, of painfully slow, unsupported attempts to make progress. Then all of of a sudden, in the course of a decade, the tipping point is reached and an entire industry blossoms into being. We are just about there for rejuvenation biotechnology; it is the end of the lengthy beginning, and the start of a great and energetic new phase of development.
It is customary, in techno-visionary circles, to base one's expectations of the future on the principle of exponentially accelerating change. The often uncannily accurate timeframe predictions of Ray Kurzweil have engendered a culture of thinking and talking in exponential terms, even when it comes to the names of conferences. Like any one-word meme, this does not tell the whole story: some aspects of technological progress pretty clearly don't proceed exponentially, and indeed some (which, mercifully, include the rate of progress necessary to maintain longevity escape velocity once we reach it) don't need to be exponential in order to achieve needed goals. But today I want to highlight the opposite phenomenon: phases during a technology's development when progress is genuinely superexponential, as with the sudden acceleration in 2007 or so in the amount of DNA that could be sequenced for a given price.
Inevitably, my sense that rejuvenation biotechnology has had a bona fide superexponential year is to a large extent subjective. However, my location at the eye of this storm gives me some basis for feeling that I'm probably basing it on good information. What is that information?
The single biggest item is the truly breathtaking rate of proliferation of private-sector involvement in this space. That proliferation has been manifest on both sides of the fence - in the number of startups seeking investment, and equally in the number of investors seeking opportunities to get involved. A comparison with the situation just twelve months ago can be made in many ways, but for me the most straightforward is the task of organizing a one-day investor-facing event in early January in San Francisco on behalf of my friends at Juvenescence. In 2018, the task of identifying a dozen companies to showcase was easy for me - that was pretty much the total number of startups I knew of in the rejuvenation space that were in a fundraising mode, and I was pretty sure that not many others existed below my radar. But I'm engaged right now in organizing the same thing for January 2019, and the situation could not be more different. Even when restricting my attention to companies located in this part of the world, I am swamped with high-quality options; and literally not a week goes by any more when I don't become aware of another one. The takeoff has been as spectacular as for the dotcom boom.
What of the other side of the fence, the investors? There the story is just as bright. A year ago, I could count the investors who were overtly focusing much, and in some cases most, of their attention on the rejuvenation space on the fingers of two hands. Now, it is no exaggeration to say that I have lost count: every single conference I speak at (and that's more than one a week on average) I am approached by an investor who is eager to learn more about how to get involved. The acceleration is staggering. The dotcom boom is again the natural comparison, and again I think the trajectory is similar.
An Approach to In Vivo Detection of Senescent Cells
The accumulation of senescent cells is an important cause of aging. These cells are created in large numbers, day in and day out, but near all are quickly destroyed, either by their own programmed cell death processes, or by the immune system. A tiny fraction linger, however, and produce a potent mix of inflammatory signals that disrupt tissue function in many ways. The more senescent cells, the worse the consequences. There are assays to detect senescent cells in tissue samples, but these tests are all quite old and cumbersome, with a limited range of application. The research community would benefit greatly from improved methods of detection of senescent cells, assays capable of greater discrimination, and particularly those that can run in a living animal. The paper noted here is a step in that direction.
Although senescent cells are well-characterized in culture, identifying senescent cells in vivo has been challenging. The inability to reliably identify senescent cells in an intact organism has impaired the study of their precise role in tumor suppression and physiological aging. To date, activation of p16INK4a expression has proven to be one of the most useful in vivo markers of senescence. The expression of p16INK4a is highly dynamic, being largely undetectable in healthy young tissues, but rising sharply in many tissues with aging or after certain sorts of tissue injury. Murine studies suggest that accumulation of p16INK4a leads to an age-related loss of replicative capacity in select tissues, thereby causing some phenotypic aspects of aging.
Our laboratory and others have placed reporter genes under the control of the p16INK4a promoter by either transgenic or knock in approaches. These reporter alleles have been employed to demonstrate that the p16INK4a promoter activity increases during wounding, inflammation, tumorigenesis, or aging in vivo in tissues. While valuable for studies at the tissue or organ level, these alleles have been limited in their ability to detect and isolate individual cells with strong activation of the p16INK4a promoter in vivo. To study individual p16INK4a-activated cells, we have generated a fluorescence-based reporter allele with tandem-dimer Tomato (tdTom) knocked into the endogenous p16INK4a locus. This allele enables the identification and isolation of p16INK4a-activated cells at the single-cell level from cultured cells and in vivo. Using this allele, we quantified tdTom+ cells in several tissues with aging or in the setting of inflammation, and isolated these cells for characterization in terms of function and gene expression.
Poor Sleep Causes Raised Levels of Tau in the Brain
Researchers here suggest a possible explanation for the observed association between disrupted sleep in later life and the development and progression of Alzheimer's disease. Sleep appears necessary to clear out tau produced during waking hours, and loss of sleep means raised levels of tau persist. The more tau in circulation, the more that an altered form of tau will be generated and aggregate into neurofibrillary tangles to damage brain cells. More research would be needed to quantify the size of this effect in comparison to, say, the contributions of lack of exercise or obesity. In the long run, however, one would hope that therapies capable of safely and efficiently clearing neurofibrillary tangles will make the whole question of contributions of this nature entirely irrelevant.
Poor sleep has long been linked with Alzheimer's disease, but researchers have understood little about how sleep disruptions drive the disease. Now, studying mice and people, researchers have found that sleep deprivation increases levels of the key Alzheimer's protein tau. And, in follow-up studies in the mice, the research team has shown that sleeplessness accelerates the spread through the brain of toxic clumps of tau - a harbinger of brain damage and decisive step along the path to dementia.
Tau is normally found in the brain - even in healthy people - but under certain conditions it can clump together into tangles that injure nearby tissue and presage cognitive decline. Recent research has shown that tau is high in older people who sleep poorly. But it wasn't clear whether lack of sleep was directly forcing tau levels upward, or if the two were associated in some other way. To find out, researchers measured tau levels in mice and people with normal and disrupted sleep. Mice are nocturnal creatures. The researchers found that tau levels in the fluid surrounding brain cells were about twice as high at night, when the animals were more awake and active, than during the day, when the mice dozed more frequently. Disturbing rest during the day caused daytime tau levels to double. Much the same effect was seen in people.
To rule out the possibility that stress or behavioral changes accounted for the changes in tau levels, researchers created genetically modified mice that could be kept awake for hours at a time by injecting them with a harmless compound. Using these mice, the researchers found that staying awake for prolonged periods causes tau levels to rise. Altogether, the findings suggest that tau is routinely released during waking hours by the normal business of thinking and doing, and then this release is decreased during sleep allowing tau to be cleared away. Sleep deprivation interrupts this cycle, allowing tau to build up and making it more likely that the protein will start accumulating into harmful tangles.
CXCL12 Promotes Small Artery Growth in Injured Hearts, but Why Not Apply this Approach in Advance of Injury as Well?
While rejuvenation research aims at a world in which no-one ever suffers coronary artery disease or a heart attack, the causes of those conditions prevented and controlled, we still live in a world in which these conditions are accepted as inevitable, and the near term focus of regenerative medicine is structural repair for the survivors after the fact. This is a poor second best, but the research community continues to develop ever better potential means of repair. In this case, in which researchers provoke greater construction of secondary arteries that can support the primary blood vessels of the heart, capable of supplying blood when the primary is damaged, one may ask whether it can also be a means of reducing the impact of structural damage if applied well in advance. Sadly, preventative medicine of this sort is a hard sell in the present regulatory environment. Applying enhancement therapies to older people still considered "healthy" is just not as acceptable a goal as it should be.
Researchers observed that patients with blockages in major arteries feeding the heart often have confoundingly different outcomes. "Some patients have a blockage in one coronary artery and die; other patients have multiple blockages in multiple areas but can run marathons." The difference may be that this second group of patients has collateral arteries, tiny arteries that bypass blockages in hearts' major arteries and feed areas of the heart starved of oxygen. "They are like the side streets that let you get around a traffic jam on the freeway." Such collateral arteries could help people with atherosclerosis or people recovering from a heart attack, except that collateral arteries are only seen in a minority of patients.
Researchers have now discovered how these collateral arteries are formed and a signaling molecule that promotes their growth in adult mice, offering hope that collateral arteries may be coaxed to grow in human patients. The researchers began by looking at newborn mice. They documented that young mouse healing was due in part to the growth of new collateral arteries into the injured area. Through advanced imaging that let them look at the intact newborn hearts at the cellular level, the researchers showed that this happened because arterial endothelial cells exited the artery, migrated along existing capillaries that extended into injured heart tissue and reassembled to form collateral arteries.
The molecule CXCL12 is an important signal during embryonic development of arterial cells, and has been shown to improve cardiac recovery and function after heart attacks. The scientists wondered if this molecule had a beneficial effect by promoting collateral artery growth in injured heart tissue. They found that CXCL12 was mostly restricted to arterial endothelial cells in uninjured neonatal mouse hearts. In newborn mice with heart injuries, it shows up in the capillaries of the injured area. The researchers found evidence that low oxygen levels in the injured area turned on genes that create CXCL12, signaling the areas to which arterial endothelial cells should migrate.
Next they investigated whether CXCL12 could help adult heart tissue grow collateral arteries. After inducing heart attacks in adult mice, they injected CXCL12 into the injured areas. Sure enough, 15 days after the injuries, there were numerous new collateral arteries formed by the detaching and migrating artery cells. Almost none were present in control mice.
The Importance of Macrophages in Kidney Regeneration
Macrophages are demonstrably important in tissue regeneration. The process of regeneration is an intricate dance of signaling and activity carried out between stem and progenitor cells, somatic cells of varying types, senescent cells, and immune cells such as macrophages. The research of recent years strongly suggests that differences in macrophage behavior are in some way fundamental to the exceptional regeneration exhibited by species as diverse as salamanders, zebrafish, and spiny mice. Can macrophage behavior in our species be beneficially adjusted to improve regenerative capacity? Comparatively simple approaches aiming to shift macrophage polarization from the inflammatory, aggressive M1 polarization to the pro-regenerative M2 polarization appear quite promising in early animal studies, but this is just the tip of the iceberg. Much is left to be explored, and articles such as this one only underline the benefits that might be achieved given success.
Acute kidney injury, or AKI, is a devastating condition that develops in two-thirds of critically ill patients, and patients with AKI have a 60 percent risk of dying. In AKI, kidneys can become scarred and can show progressive decline in function, becoming unable to heal their tissue. During development in the womb, immune cells called macrophages go to the kidneys, and they remain there for life. Researchers have found that, during AKI in a mouse model, the kidney-resident macrophages are reprogrammed to a developmental state, resembling these same cells when they are found in newborn mice. Newborn mouse kidneys are still developing. This reprogramming during AKI may be important to promote healing and tissue regeneration. If a similar developmental shift is seen for human kidney-resident macrophages during AKI, that could aid new therapeutic approaches for patients.
Researchers detailed how the kidney-resident macrophages are reprogrammed to a developmental state after injury. In response to the disease model, the kidney-resident macrophages turned off their expression of major histocompatibility complex type II, or MHCII. This lack of expression is similar to kidney-resident macrophages in newborn mice - those mice, the researchers showed, lack expression of this protein up to postnatal day seven, and then begin to express it over the next two weeks. Notably, MHCII protein and macrophages have important roles in autoimmunity and transplant rejection.
In addition, kidney-resident macrophages after AKI underwent transcriptional reprogramming to express a gene profile closely resembling that of the kidney-resident macrophages in newborn mice at postnatal day seven. Further supporting their role in development and healing, the reprogrammed kidney-resident macrophages were enriched in Wnt signaling, an active pathway that is vital for mouse and human kidney development. Many basic science research studies have suggested the importance for tissue-resident macrophages in healing after injury, but development of therapies promoting them is still in early stages.
Hypertension May Accelerate Neurodegeneration by Reducing Clearance of Metabolic Waste via Cerebrospinal Fluid Drainage
I missed the open access paper noted here when it appeared last year. It is an interesting addition to the growing body of evidence that shows drainage of cerebrospinal fluid from the brain to be an important mechanism for clearance of metabolic waste. That the drainage paths become impaired with age contributes to the aggregation of proteins such as amyloid-β, involved in the development of Alzheimer's disease. Thus approaches to restore drainage in one way or another should prove quite effective for a range of neurodegenerative conditions. We will find out whether or not this is the case over the next few years as groups like Leucadia and EnClear move beyond animal studies and into human trials.
Cerebrospinal fluid (CSF) aids in the removal of metabolic waste from the brain. The exact anatomical pathways and mechanisms underlying how solutes in the interstitial fluid (ISF) are transported towards CSF remain unclear. Historically, it has been thought that solutes exit the brain along a network of perivascular spaces (PVSs) surrounding cerebral arteries, against the direction of blood flow. Recent in vivo experiments in rodents have shown the opposite: CSF enters the brain along arterial PVSs, and this flow plays a vital role in driving the clearance of amyloid-β (Aβ) from the ISF at more downstream locations
In both cases, indirect experimental evidence suggests that fluid within PVSs is transported via bulk flow and possibly driven by arterial pulsations derived from the cardiac cycle. To evaluate fluid motion within the PVS we have adapted in vivo two-photon imaging to allow measurement of CSF flow speeds simultaneously with recordings of cardiac and respiratory cycles. We have also performed synchronized measurements of the artery diameter and heartbeat to determine vessel wall dynamics. The analysis confirms that CSF bulk flow in the PVS is pulsatile, at the same frequency as the cardiac cycle, and in the same direction as blood flow. Our results are highly consistent with a fluid transport mechanism - perivascular pumping - wherein vascular wall kinetics directly drive pulsatile CSF bulk flow in the PVS.
Finally, we show that high blood pressure, a condition that affects close to half of the world's adult population, disrupts the perivascular pump and sharply slows CSF transport in the PVS. Earlier studies have shown that arterial hypertension promotes the accumulation and aggregation of Aβ. We speculate that hypertension-induced reduction of PVS fluid transport contributes directly to the associations between arterial hypertension and Alzheimer's disease.
The Interactions of Frailty, Exercise, and Risk of Dementia
Frailty is a consequence of advanced aging, a categorization applied to an individual who is greatly physically weakened by the accumulation of cell and tissue damage and its many downstream consequences. Frailty is generally described as some combination of the loss of muscle mass and strength known as sarcopenia, fragility of bones caused by osteoporosis, and a faltering immune system that no longer adequately protects against pathogens, coupled with outcomes such as weakness, exhaustion, and weight loss. The underlying root causes of frailty are also the causes of other age-related conditions, and it is thus expected to find that frail individuals also exhibit a greater incidence of a range of conditions, such as dementia.
How is it that some people can have a brain full of plaques and tangles, yet somehow fend off dementia? Researchers analyzed postmortem data from 456 participants in the Rush Memory and Aging Project (MAP). At their last visit before death, 242 had a diagnosis of possible or probable Alzheimer's disease (AD). Using information gathered from past clinical visits, the researchers calculated a frailty index for each based on a 41-item questionnaire that assessed age-related symptoms, morbidities, and functional deficits. The final score represented a fraction of the total possible deficits. For this cohort, who averaged 89.7 years of age at death, the mean frailty index was 0.42, right at the threshold between moderately and severely frail.
Compared with people who were less frail, those whose frailty was above average were older, likelier to have been diagnosed with AD dementia, and had a higher burden of amyloid-β plaques and tau tangles at autopsy. Thirty-five participants who had not been diagnosed with dementia, but who had a high burden of plaques and tangles, turned out to have low frailty scores. On the other side of the spectrum, 50 who had been diagnosed with dementia but had little AD pathology had the highest frailty indexes. Overall, the findings tied frailty to dementia, and suggested that less frail people are better able to withstand a given amount of AD pathology than their more fragile counterparts.
Could dementia have caused the frailty? The researchers could not rule out reverse causality with their cross-sectional data. However, they did find that the relationship among frailty, pathology, and dementia remained even when they corrected the frailty index for functional deficits that can be caused by dementia, or when they controlled for known dementia risk factors, including stroke and hypertension. The findings suggest that the clinical manifestation of AD depends not just on its neuropathology, but also on the extent of the aging process. People age at different rates, and those who do so more rapidly will not only be more likely to develop AD pathology, but also be more sensitive to it. On a positive note, the findings suggest that slowing the broader process of aging - via changes in lifestyle and/or anti-aging therapeutics - might also prevent dementia.
Aerobic Exercise Reduces Cancer Incidence and Age-Related Inflammation in Mice
Regular aerobic exercise, like calorie restriction, improves near all aspects of health throughout the life span. Unlike calorie restriction, exercise doesn't slow aging in the sense of improving life span. It does reduce incidence of many age-related diseases, extending the proportion of life spent in good health, however. Aging is a complicated many-faceted web of cause and consequence, and these two very robust metabolic alterations, exercise and calorie restriction, illustrate this point by the different character of the alterations in aging and age-related disease they produce. That it is possible to have less of most age-related disease but not live longer is a peculiarity of the distribution of affected mechanisms. It would be interesting to look at the set of calorie restriction associated mechanisms that are not also touched on by exercise, and vice versa, but that is (a) poorly mapped at this time, and (b) both sets are very large and incompletely understood. The memo for humans is to practice both interventions.
Biological aging is associated with progressive damage accumulation, loss of organ reserves, and systemic inflammation ('inflammaging'), which predispose for a wide spectrum of chronic diseases, including several types of cancer. In contrast, aerobic exercise training (AET) reduces inflammation, lowers all-cause mortality, and enhances both health and lifespan. In this study, we examined the benefits of early-onset, lifelong AET on predictors of health, inflammation, and cancer incidence in a naturally aging mouse model.
Lifelong, voluntary wheel-running (O-AET; 26-month-old) prevented age-related declines in aerobic fitness and motor coordination vs. age-matched, sedentary controls (O-SED). AET also provided partial protection against sarcopenia, dynapenia, testicular atrophy, and overall organ pathology, hence augmenting the 'physiologic reserve' of lifelong runners. Systemic inflammation, as evidenced by a chronic elevation in 17 of 18 pro- and anti-inflammatory cytokines and chemokines, was potently mitigated by lifelong AET, including master regulators of the cytokine cascade and cancer progression (IL-1β, TNF-α, and IL-6).
In addition, circulating SPARC, previously known to be upregulated in metabolic disease, was elevated in old, sedentary mice, but was normalized to young control levels in lifelong runners. Remarkably, malignant tumours were also completely absent in the O-AET group, whereas they were present in the brain (pituitary), liver, spleen, and intestines of sedentary mice. Collectively, our results indicate that early-onset, lifelong running dampens inflammaging, protects against multiple cancer types, and extends healthspan of naturally-aged mice.
Reduced Blood Pressure Lowers Risk of Mild Cognitive Impairment, but Not Dementia?
Data from a large human trial has shown that control of blood pressure in older individuals, achieved through lifestyle changes and medication, reduces the risk of mild cognitive impairment by 20% or so, but not the risk of dementia. This is a nuanced result; given what is known of the way in which blood pressure interacts unfavorably with a range of mechanisms related to the development of dementia, it is certainly easier to blame the study design, as the authors do here. There is plenty of evidence to show that hypertension damages the brain directly, causing a greater incidence of ruptured capillaries and tiny areas of dead tissue. It may also cause removal of metabolic waste to decline, contributing to the buildup of protein aggregates that progressively impairs the operation of the mind. It may change the behavior of immune cells in the brain for the worse. Further, the epidemiological data also exhibits a very good correlation between hypertension and dementia. So on the whole, the outcome of this study is a puzzle, and doesn't fit well with the established data on the subject.
Intensive lowering of blood pressure did not significantly reduce dementia risk but did have a measurable impact on mild cognitive impairment (MCI), according to the final, peer-reviewed results from the Systolic Blood Pressure Intervention Trial (SPRINT) Memory and Cognition in Decreased Hypertension (SPRINT MIND). SPRINT MIND secondary results are the first to show an intervention that significantly reduces the occurrence of MCI, which is a well-established precursor of dementia. MCI is a condition in which people have more difficulty with cognition, thinking, remembering, and reasoning, than normal for people their age. Dementia is a more severe form of loss in cognitive functions that interferes with daily life. Alzheimer's disease is the most common type of dementia. High blood pressure, or hypertension, is very common in persons over the age of 50 and a leading risk factor for heart disease, stroke, kidney failure, and a growing body of research suggests that it may increase risk for dementia later in life.
The participants in SPRINT were adults 50 years and older at high risk for cardiovascular disease. Results of the SPRINT trial, which ended early, showed that intensive blood pressure control, i.e., a systolic blood pressure target of less than 120 mmHg, compared to a standard target of less than 140 mmHg, reduced cardiovascular events and overall mortality. Between November 2010 and March 2013 more than 9,300 participants were randomized to the two target groups with nearly 4,700 in each group. In August 2015, the SPRINT trial was stopped after 3.3 years of treatment when the major beneficial effects of intensive blood pressure management on mortality and cardiovascular disease were discovered. Assessment for development of dementia and MCI continued for the full planned five years.
SPRINT MIND aimed to address whether intensive blood pressure control would also reduce the risk of developing dementia and cognitive impairment over the ensuing five years. Cognitive assessments were given to participants who had high blood pressure but no history of stroke or diabetes at the start of the trial, and over 91 percent had at least one follow up. Participants were classified into one of three categories: no cognitive impairment, MCI, or probable dementia.
The primary results of this analysis found no statistically significant difference between standard and intensive treatment in the proportion of participants that were diagnosed with dementia. The study, however, had fewer cases of dementia than expected. Nevertheless, the secondary results suggested that the intensive treatment reduced the risk of MCI and the combined risk of MCI and dementia. Due to the success of the SPRINT trial on the cardiovascular outcomes, the study intervention was stopped early; as a result, participants were treated for a shorter period than originally planned. The authors concluded that the shorter time and the unexpected fewer cases of dementia may have made it difficult to determine the role of intensive blood pressure control on dementia.