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- Calcium Alpha-Ketoglutarate Supplementation Reduces Epigenetic Age in Humans
- Brd2 Inhibition as an Approach to Slow Aging
- The Aging Gut Microbiome Produces More Trimethylamine, Harming Arterial Function
- MicroRNA-34a Promotes Vascular Cellular Senescence and Consequent Calcification
- It is Challenging to Find Support for Evolutionary Trade-offs Between Reproduction and Aging in Human Data
- A2B Receptor Upregulation in Mice Increases Muscle Mass, Diminishes Fat Mass
- Near-Infrared Light Exposure Modestly Improves Visual Function in Older People
- Reviewing Adult Neurogenesis in the Mammalian Brain
- Sedentary Behavior Correlates with Raised Risk of Age-Related Disease
- Exercise Slows Inappropriate Growth of Blood Vessels in a Mouse Model of Macular Degeneration
- Cortisol Declines in the Old, Causing Macrophages to Become More Inflammatory
- Why Do Older Mothers Produce Less Robust Offspring?
- Ex Vivo Mitochondrial Transfer as a Way to Improve Stem Cell Therapy Outcomes
- Differences in Exosome MicroRNA Content Following Exercise in Sedentary versus Fit Older People
- Stem Cell Exhaustion in the Aging Lung
Calcium Alpha-Ketoglutarate Supplementation Reduces Epigenetic Age in Humans
The company Ponce De Leon Health claims that a recent pilot study of calcium alpha-ketoglutarate supplementation results in an average reduction of 8.5 years of epigenetic age via the DNA methylation test offered by TrueMe Labs. This being the supplement industry, expect to have to wade through a lot of dubious and excessive marketing to find any solid information about what actually happened here. The best pace to start is with the 2019 paper on the effects of calcium alpha-ketoglutarate in mice, which is a reputable study authored by reputable researchers. Delivered late in life, this intervention reduced frailty to a meaningful degree, but with only a modest effect on life span. It did not reduce senescent cell burden, but did reduce inflammatory signaling - and chronic inflammation is an important aspect of degenerative aging.
The important point to consider here is that the TrueMe Labs assay is not a relabeling of any of the more established epigenetic clocks, those with significant research associated with their behavior. It is is its own beast, an independently developed test. It uses only 13 DNA methylation sites, and so it is very possible that it is much more sensitive to some interventions than others, in comparison to, say, the original Horvath clock, depending on which mechanisms influence those sites. Thus one cannot take any of the established research into the better studied clocks and use it to inform expectations as to how the TrueMe Labs assay will behave. 8.5 years might sound like a large effect size, but it is impossible to say whether or not that is the case.
That is the challenge with all epigenetic clocks, frankly. None are yet strongly connected to underlying mechanisms of aging; it is hard to say what any specific change or outcome actually represents in terms of metabolic processes. The assays will produce a number, but that number cannot be compared between clocks, and it cannot be compared between interventions. It cannot even be used to say how good any specific intervention might be, without a great deal of further calibration for that specific intervention. Not that one would learn that by reading the Ponce De Leon Health marketing materials. A cynic might suggest that they shopped for the clock that would produce the most sizable outcome for their intervention. Whether or not that is the case here, I'm sure that this strategy will become prevalent.
Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice
Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes that include collagen synthesis and epigenetic changes.
Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.
Pilot Study Results Suggest Epigenetic Age Reversal
Ponce de Leon Health initially worked with Dr. Brian Kennedy, who was, at the time, based at the Buck Institute for Research on Aging, searching for compounds that were generally recognized as safe (GRAS) but that had the potential to influence aging in mammals. The company screened over 300 GRAS compounds and identified compounds that could modulate a number of pathways that are linked to aging. Dr. Kennedy subsequently joined Ponce de Leon Health as its Chief Scientific Officer, and the company has been busy testing and preparing to translate these findings to people. Its strategy has been to test its products on mammalian models that closely emulate human aging in order to give the best chance of translating beneficial results to us.
For consumer testing the company gave participants Rejuvant and measured their epigenetic ages using DNA methylation testing. This supplement contains a proprietary form of calcium alpha-ketoglutarate, which the FDA considers to be GRAS. The company believes that Rejuvant works by slowing down the rate of age-related DNA methylation and reducing the inflammation caused by senescent cells, two proposed reasons why we age.
Brd2 Inhibition as an Approach to Slow Aging
There are innumerable studies showing small gains in mouse life span. Most cannot be reproduced, particularly the older ones, those that took place before it was common knowledge in the research community that one has to very aggressively control for accidental calorie restriction. If an intervention makes mice eat less, then they will tend to live longer, even if the intervention is modestly toxic. The improvements to health and longevity produced by calorie restriction in short-lived species are larger than near all other interventions assessed to date.
Nonetheless, mechanisms that reliably (and usually modestly) slow aging in short-lived species do exist, acting to adjust metabolism into a more favorable state. Many are connected to calorie restriction, in which stress response processes are upregulated, and are as a consequence fairly well studied. Numerous interventions exist to manipulate these mechanisms, but it is not expected that sizable results in mice will translate to sizable results in humans, at least not for this class of approach. The benefit to longevity is observed to scale down as species life span increases. This may be because famine is seasonal, and thus evolutionary adaptation that allows passage through famine to reproduce on the other side must produce proportionally larger gains in life span in short-lived species than in long-lived species.
Interestingly, the intervention described in today's open access paper was an accidental discovery by researchers working outside the field of aging research. A gene related to epilepsy, Brd2, turned out to be connected to a number of longevity-associated cellular processes. Inhibition of Brd2 extends mouse life span by a large enough amount to suggest that it is a real effect, though by much less than is achieved via calorie restriction.
Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice
Although it is thought that aging results from the cumulative effects of molecular and cellular damage, we serendipitously discovered that a Brd2-haploinsufficient (Brd2+/-; denoted HET) mouse model we developed to study epilepsy had a much longer lifespan compared to wild type (Brd2+/+; denoted WT) mice. In pursuing the mechanism by which BRD2, a bromodomain (BET) protein, predisposed to epilepsy, we found that HETs, which are overtly normal, not only have significantly longer lifespans but also show healthier-aging phenotypes, including reduced cancer incidence and improved kidney function, as compared to wildtype mice.
There are several genes and molecular processes that are known to influence longevity in mice. Many of those genes are in turn influenced by Brd2. For example, Brd2 haploinsufficiency downregulates IGF signaling, and IGF signaling is decreased in calorically restricted mice - a dietary intervention that increases lifespan. Similarly, Brd2 haploinsufficiency up-regulates genes in the Sirtuin pathway, and up-regulation of the Sirtuin pathway is associated with increased lifespan. Specifically, Sirtuin 1 (SIRT1) and its homologs regulate longevity-related processes such as DNA repair, genome stability, inflammation, apoptosis, cell cycle progression and mitochondrial respiration. Reduced expression of Brd2 also increases p53, Nqo1, and Hmox1 expression, all of which reduce oxidative stress. In addition, upregulation of p53 increases genomic stability, promotes DNA repair, and increases lifespan. Because Brd2 haploinsufficiency is tied to multiple longevity-related genes and molecular processes, reduced expression of Brd2 could be a fundamental - and heritable - factor influencing lifespan.
Here, we show that Brd2 haploinsufficiency (Brd2+/-) extends lifespan and increases healthspan in C57B6/J mice. In Brd2+/- mice, longevity is increased by 23%, and, relative to wildtype animals (Brd2+/+), cancer incidence is reduced by 43%. In addition, relative to age-matched wildtype mice, Brd2 heterozygotes show healthier aging including: improved grooming, extended period of fertility, and lack of age-related decline in kidney function and morphology. Our data support a role for haploinsufficiency of Brd2 in promoting healthy aging. We hypothesize that Brd2 affects aging by protecting against the accumulation of molecular and cellular damage. Given the recent advances in the development of BET inhibitors, our research provides impetus to test drugs that target BRD2 as a way to understand and treat/prevent age-related diseases.
The Aging Gut Microbiome Produces More Trimethylamine, Harming Arterial Function
In recent years academic interest has grown in the study of the gut microbiome. Researchers are making inroads into understanding the considerable influence of these microbial populations over the progression of health and aging. The gut microbiome may be as influential as physical activity in these matters. The balance of microbial populations shifts unfavorably over time, for reasons that are yet to be fully mapped and understood. This leads to greater numbers of inflammatory microbes, or those that produce harmful byproducts, and fewer microbes that produce beneficial metabolites. Researchers have identified some of the more important beneficial metabolites that decline with age, such as indoles, butyrate, and propionate. In the research materials I'll point out today, the authors note a harmful metabolite, trimethylamine, that is produced in greater amounts in older individuals.
What to do about these issues? It is possible in principle to supplement missing metabolites, as they are identified. Removal of harmful metabolites is more challenging as a general rule, for all that it seems plausible in the specific case of trimelthylamine. A better approach to the problem is to fix the age-related disruption of the microbiome. Various options exist: fecal microbiota transplants, for example, are already used in human medicine, and transplanting young microbes into old individuals has been shown to be beneficial in animal studies, a method to reset the balance of microbial populations. Equally, less comprehensive methods such as innoculation against flagellin, to rouse the immune system into destroying more of the harmful microbes present in the gut, are also possible. It is also the case that very aggressive use of probiotics might work, though not yet all that well explored at the high doses likely required.
What makes arteries age? Study explores new link to gut bacteria, diet
Eat a slab of steak or a plate of scrambled eggs, and your resident gut bacteria get to work immediately to break it down. As they metabolize the amino acids L-carnitine and choline, they churn out a metabolic byproduct called trimethylamine, which the liver converts to trimethylamine-N-Oxide (TMAO) and sends coursing through your bloodstream. Previous studies have shown that people with higher blood levels of TMAO are more than twice as likely to have a heart attack or stroke and tend to die earlier. But to date, scientists haven't completely understood why.
The researchers measured the blood and arterial health of 101 older adults and 22 young adults and found that TMAO levels significantly rise with age. (This falls in line with a previous study in mice, showing the gut microbiome - or your collection of intestinal bacteria - changes with age, breeding more bacteria that help produce TMAO). Adults with higher blood levels of TMAO had significantly worse artery function, the new study found, and showed greater signs of oxidative stress, or tissue damage, in the lining of their blood vessels. When the researchers fed TMAO directly to young mice, their blood vessels swiftly aged.
Preliminary data also show that mice with higher levels of TMAO exhibit decreases in learning and memory, suggesting the compound could also play a role in age-related cognitive decline. On the flip side, old mice that ate a compound called dimethyl butanol (found in trace amounts in olive oil, vinegar and red wine) saw their vascular dysfunction reverse. Scientists believe that this compound prevents the production of TMAO. Everyone - even a young vegan - produces some TMAO. But over time, eating a lot of animal products may take a toll.
Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans
Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation.
In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation. Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events.
Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation.
Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide.
MicroRNA-34a Promotes Vascular Cellular Senescence and Consequent Calcification
With the growing interest in the accumulation of senescent cells as an important cause of aging, and more funding flowing into this part of the field, researchers are uncovering numerous direct links between cellular senescence and age-related conditions. Senescent cells cause harm to tissues via their inflammatory secretions, the senescence-associated secretory phenotype (SASP). The SASP is damaging, but there are usually too few senescent cells, even in later life, to have a significant effect on tissue dysfunction through their localized actions. There may be exceptions to that rule, but the evidence to date strongly suggests that the SASP is the dominant mechanism in the contribution of cellular senescence to degenerative aging.
One of the many conditions in which cellular senescence is implicated is vascular calcification, the inappropriate deposition of calcium that stiffens blood vessels and heart tissue. Senescence causes some cells, senescent cells and others, triggered by the SASP, to behave as though they are maintaining bone. Stiffening of blood vessels causes the chronic raised blood pressure of hypertension and consequent pressure damage to fragile tissues throughout the body and brain. This downstream harm is so important that forcing a lower blood pressure can significantly reduce age-related mortality, even without addressing the deeper causes.
The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification
The deterioration of arterial anatomy and physiology that occurs during chronological aging is a risk factor for cardiovascular morbidity and all-cause mortality. Aged arteries are characterized by functional changes of vascular smooth muscle cells (VSMCs) from a contractile and quiescent status to a senescent phenotype. VSMCs approaching senescence acquire the senescence-associated secretory phenotype (SASP) that consists of the secretion of a variety of soluble molecules, mostly pro-inflammatory cytokines and chemokines, growth factors, and matrix-remodeling enzymes. SASP factors are released in the blood circulation and act locally in a paracrine manner to spread senescence to neighboring cells; in this way, they contribute to the development of a sterile, low-grade, chronic age-associated systemic and tissues inflammation known as "inflammaging" considered the main risk factor for the most common age related diseases, included cardiovascular diseases.
Senescent VSMCs express bone-related genes, like Runt-related transcription factor 2 (Runx2), alkaline phosphatase, and osteocalcin that favor their maladaptive switching to an osteoblastic phenotype and eventually, the onset of vascular calcification (VC), a cardiovascular complication characterized by hydroxyapatite crystals deposition and mineralization of the arterial wall. Accordingly, during aging or in pathological conditions including chronic kidney disease (CKD), atherosclerosis, or type 2 diabetes (T2D), the molecular mechanisms that promote VSMCs senescence support their osteogenic transdifferentiation and VC.
MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors, and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J Mir34a-/- mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.
It is Challenging to Find Support for Evolutionary Trade-offs Between Reproduction and Aging in Human Data
The disposibility theory of aging is one of numerous evolutionary theories of aging that seek to explain why aging exists and is near universal across species. In this case, aging is viewed as the inevitable result of trade-offs between resources allocated to reproduction versus resources allocated to tissue maintenance. Like near all evolutionary theories, and particularly those relating to aging, the models and the science are much debated.
Since there is some variation between individuals within a species, one should expect to find a distribution of outcomes for any given trade-off when comparing large numbers of individuals of a given species. In this case, for this view of the origin of aging, we should expect to see that greater reproductive success correlates with a worse outcome in later life. Meaning a faster decline, more age-related disease, and a shorter life expectancy.
In today's open access paper, researchers compare parity (number of children carried to term) with later frailty in a human population. They indeed observe that more births tends to correlate with greater age-related frailty. The challenge with human data is that one can always come up with other plausible explanations for this effect, completely unrelated to fundamental biology. That the effect is similar in men and women somewhat sabotages any thoughts of a biological or physiological cost to childbirth as a dominant mechanism, for example.
Frailty: A cost incurred by reproduction?
The disposability theory of ageing proposes that investing in reproduction, at the cost of somatic maintenance, leads to senescence. In humans, the theory predicts that those with more children will have shorter lives. Researchers used a historical dataset from the British aristocracy to demonstrate that females with the longest life span had fewer children relative to the whole sample. Indeed, almost 50% of females who lived to 80 years and over were childless. A similar relationship between parity and longevity was found in males. The paper was criticized in the literature, particularly with regards to the quality of the data. Despite a sustained research effort and strong theoretical expectations, evidence to support a reproduction-longevity trade-off in humans is not strong. Studies of historical and contemporary cohorts have not found a consistent association between parity and longevity - no association, as well as positive and negative associations, have all been reported.
Most studies to date have tested evolutionary theories of senescence by focusing on the relationship between parity and survival (usually measured in terms of longevity). However, it is possible that survival is too crude a measure of senescence and, as a result, the 'real' cost incurred by reproduction has not been elucidated. Whilst studies have examined other health outcomes, such as physical, functional and cognitive impairment, self-rated health and limiting long-term illnesses in older males and females, findings have not been consistent. Examining the relationships between parity and individual domains of health may not be the best methodology to address the hypothesis because impairment profiles vary significantly in the older adult population and measures of individual domains do not capture all adults with poor health. 'Frailty', on the other hand, is a multidimensional measure of health status that may help to better define the long-term consequences (whether they be harms or benefits) of human reproduction.
The aims of this study were to examine the cross-sectional relationship between parity and later life frailty (represented by the Frailty Index) and to explore whether this relationship is influenced by sex. Data from the English Longitudinal Study of Ageing (ELSA) were used to test two key hypotheses: firstly, that higher parity is associated with greater frailty, indicating a 'parity-frailty trade-off' and secondly, that sex differences in frailty are greater at higher parities than at lower parities due to sex differences in the physiological costs of childbearing.
We found that the most parous adults were the most frail, providing weak evidence for a 'parity-frailty trade-off'. The relationship between parity and frailty was similar for both sexes, and thus the results suggest that behavioral and social factors associated with rearing many children may be more relevant to the parity-frailty relationship than the physiological burden of childbearing. Parity-frailty trade-off may manifest in older males and females with high parity due to economic strain, disruption of occupational attainment, and psychological stress. In addition, high parity may negatively influence lifestyle habits such as dietary choices and physical activity in both sexes. These behavioural factors increase the risk of obesity and its metabolic complications, which in turn, increase the risk of frailty.
An alternative theory is that selection effects confound the relationship between high parity and frailty. For example, lower levels of education level are associated with particular reproductive characteristics, such as early parenthood and higher overall parity, as well as later life frailty. However, in this study, education was not found to have a significant impact on the parity-frailty relationship.
A2B Receptor Upregulation in Mice Increases Muscle Mass, Diminishes Fat Mass
Researchers here report on an interesting discovery: upregulation of a single protein, A2B receptor, adjusts metabolism in mice in the direction of more muscle mass and less fat mass. This treatment can reverse some of the normal trajectory of aging for muscle and fat mass in older animals, turning back muscle loss and fat gain. This is one of a number of similar desirable enhancements to cellular metabolism discovered over the past few decades - see the work on follistatin upregulation, for example. It is typically a long road from this sort of discovery in mice to initial tests in human subjects, particularly given the lack of any existing approved A2B receptor agonist drugs.
On their surface, cells carry numerous different "antennas", called receptors, which can receive specific signal molecules. These then trigger a specific reaction in the cell. One of these antennas is the A2B receptor. The surfaces of some cells are virtually teeming with it, for example in the so-called brown adipose tissue. Brown adipose tissue, unlike its white-colored counterpart, is not used to store fat. Instead, it burns fat and thereby generates heat.
"We took a closer look at the A2B receptors in brown adipose tissue. In the course of this we discovered an interesting association: The more A2B a mouse produces, the more heat it generates." Which means the A2B antennas somehow seem to increase the activity of the brown fat cells. But a second observation was even more exciting: Despite their increased fat burning, the animals weigh hardly less than mice with fewer receptors. They are slimmer, but at the same time have more muscles. In fact, the researchers were able to show that the muscle cells of mice also carry the A2B receptor. When this is stimulated by a small molecule agonist, muscle growth in the rodents is increased.
As they age, mice increasingly lose muscle mass - similar to humans. And just like us, they also tend to gain a lot of fat around the hips over the years. However, if they receive the agonist that activates the A2B receptor, these aging effects are inhibited. Their oxygen consumption (an indicator of energy dissiption) increases by almost half; moreover, after four weeks of treatment they have as much muscle mass as a young animal. In order to see whether the results were also meaningful for humans, the researchers examined human cell cultures and tissue samples. They found that in people with a large number of A2B receptors, the brown adipose tissue works at a higher rate. At the same time, their muscle cells consume more energy, which may indicate that they are also more active and may be more likely to be regenerated.
Near-Infrared Light Exposure Modestly Improves Visual Function in Older People
There is some evidence for near-infrared light to stimulate mitochondrial function and thus improve cell and tissue function where mitochondrial function has been impaired, such as in aging. It has been tested in models of Parkinson's disease, in which mitochondrial dysfunction is known to be important, and here researchers provide evidence for it to help compensate for failing photoreceptor function in age-related retinal degeneration. It is worth noting that improved mitochondrial function is a hypothesis to explain the observed benefits - which are quite modest in the grand scheme of things. It is a plausible hypothesis, but how exactly near-infrared light is producing this outcome is not yet fully understood.
In humans around 40 years-old, cells in the eye's retina begin to age, and the pace of this ageing is caused, in part, when the cell's mitochondria, whose role is to produce energy (known as ATP) and boost cell function, also start to decline. Mitochondrial density is greatest in the retina's photoreceptor cells, which have high energy demands. As a result, the retina ages faster than other organs, with a 70% ATP reduction over life, causing a significant decline in photoreceptor function as they lack the energy to perform their normal role.
Researchers built on their previous findings in mice, bumblebees, and fruit flies, which all found significant improvements in the function of the retina's photoreceptors when their eyes were exposed to 670 nanometre (long wavelength) deep red light. "Mitochondria have specific light absorbance characteristics influencing their performance: longer wavelengths spanning 650 to 1000nm are absorbed and improve mitochondrial performance to increase energy production."
For the study, 24 people (12 male, 12 female), aged between 28 and 72, who had no ocular disease, were recruited. All participants' eyes were tested for the sensitivity of their rods and cones at the start of the study. Rod sensitivity was measured in dark adapted eyes (with pupils dilated) by asking participants to detect dim light signals in the dark, and cone function was tested by subjects identifying coloured letters that had very low contrast and appeared increasingly blurred, a process called colour contrast.
Researchers found the 670nm light had no impact in younger individuals, but in those around 40 years and over, significant improvements were obtained. Cone colour contrast sensitivity (the ability to detect colours) improved by up to 20% in some people aged around 40 and over. Improvements were more significant in the blue part of the colour spectrum that is more vulnerable in ageing. Rod sensitivity (the ability to see in low light) also improved significantly in those aged around 40 and over, though less than colour contrast.
Reviewing Adult Neurogenesis in the Mammalian Brain
Whether and how specific portions of the adult brain produce new neurons and integrate them into functional neural circuits, a process known as neurogenesis, is of great importance to the future of regenerative medicine for the brain. It is probably easier to beneficially adjust the operation of existing tissue maintenance mechanisms than to safely deliver cells to a tissue that has no such capacity for regeneration. In the brain in particular, fine structure is enormously important to function, so comparatively blunt approaches to the delivery of replacement cells may prove challenging to implement safely.
In mammals, neural stem cells (NSCs) in the early embryonic period are called neuroepithelial cells. In the adult brain, most NSCs are quiescent. However, NSCs in the ventricular-subventricular zone (V-SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) slowly divide to generate transit amplifying progenitor cells (TAPs) via a state called activated neural stem cells (aNSC) and thus generate new neurons. Such adult neurogenesis in the mammalian brain was first suggested in the 1960s, and neurogenesis has been found to occur primarily in the V-SVZ and SGZ throughout life. New neurons generated in these two neurogenic areas are incorporated into neural circuits and play important roles.
The attenuation of adult neurogenesis in the V-SVZ has been reported to cause abnormal olfactory and sexual behavior in mice. In addition, new neurons generated in the SGZ are also integrated into DG neural circuits and play an important role in the formation of short-term memory. The attenuation of neurogenesis in the mouse SGZ has been reported to result in the impairment of new memory formation. These new neurons are also important for the formation of spatial memories. Furthermore, new integrated neurons in the DG have the function of organizing past memories and alleviating the stress response. However, adult neurogenesis decreases with age, mainly due to a decrease in NSCs and TAPs. Several studies have reported that this reduction is likely to be caused by decreases in extrinsic signals that support the proliferation of NSCs, including mitotic signals such as EGF and FGF-2, and increases in systemic pro-aging factors.
Since the existence of adult NSCs and adult neurogenesis was confirmed, studies on adult neurogenesis have been intensively conducted with the expectation of applying NSCs and neurogenesis for regenerative medicine. Although the mobilization of endogenous NSCs has been studied as one of regenerative approaches to restore lost brain function in cerebrovascular diseases, traumatic brain injuries, neurodegenerative diseases, etc., there are still many issues to be solved, such as the depletion of NSCs and the directed migration of new neurons. From a fundamental point of view, identifying the regulatory mechanisms of adult neurogenesis and its age-related decline will undoubtedly lead to future regenerative medicine strategies.
Sedentary Behavior Correlates with Raised Risk of Age-Related Disease
It is well established that sedentary behavior correlates with a greater risk of age-related disease, higher mortality, and shorter life expectancy. It is tough to prove the direction of causation when using human epidemiological data, however, meaning whether it is the case that exercise is beneficial to health, or, alternatively, that more robust people tend to exercise more. Data from animal studies robustly demonstrates that a lack of exercise is harmful to long-term health, however. It would be surprising for that not to hold up in humans.
As people age, maintaining sufficient physical activity (PA) levels is especially important as physiological decline begins to accelerate after the age of fifty. Sarcopenic changes in the muscle are associated with a decline in resting metabolic rate and glucose metabolism, contributing to increased fat accumulation and insulin resistance. Over time, these changes may negatively affect blood pressure, metabolic function, and overall cardiovascular health. Physical activity has been shown to attenuate the rate and degree to which these cardiometabolic changes occur. However, despite the well-known health benefits of PA, fewer than 30% of adults over the age of 50 engage in the recommended amount of moderate-to-vigorous PA (MVPA).
The high prevalence of sedentary behavior (SB) among older adults is of significant concern as it likely contributes to the minimization of time spent in PA. More than 25% of older adults engage in 6 hours or more of SB daily. Many cardiometabolic outcomes could be improved simply if older adults reduced their SB by increasing the time they spend in light PA (LPA). For many older adults, this is likely a more achievable and realistic goal than increasing time spent in MVPA.
Data was drawn from a convenience sample of 54 community-dwelling individuals (12 males, 42 females; mean age = 72.6 ± 6.8 years). Cardiometabolic biomarkers assessed included systolic blood pressure (SBP) and diastolic blood pressure (DBP), body mass index, waist circumference, and fasting blood glucose and cholesterol parameters. SB was assessed via accelerometry over a 7-day period, and measures included daily time in SB, number and length of sedentary bouts, the number and length of breaks between sedentary bouts, moderate-to-vigorous physical activity (MVPA), and light physical activity (LPA).
Adjusted regression analyses showed that daily sedentary time was positively associated with DBP and inversely associated with HDL cholesterol. Sedentary bout length was also associated with DBP and HDL cholesterol. Replacement of 10 minutes of SB a day with LPA was associated with improved DBP and HDL cholesterol. In conclusion, sitting for prolonged periods of time without interruption is unfavorably associated with DBP and HDL cholesterol.
Exercise Slows Inappropriate Growth of Blood Vessels in a Mouse Model of Macular Degeneration
Excessive growth of blood vessels beneath the retina is a proximate cause of blindness in conditions such as macular degeneration. Researchers here provide evidence for physical activity to be influential in the pace at which this process of tissue damage takes place. The usual conclusion to such research is provided, which is to head off into the space of developing pharmaceuticals to mimic some fraction of the effects of exercise on metabolism. Given that calorie restriction mimetic research has been ongoing for more than 20 years, with all too little to show for it, no-one should be holding their breath awaiting viable exercise mimetic drugs with meaningfully large effect sizes.
Exercise reduced the harmful overgrowth of blood vessels in the eyes of lab mice by up to 45%. This tangle of blood vessels is a key contributor to macular degeneration and several other eye diseases. The study represents the first experimental evidence showing that exercise can reduce the severity of macular degeneration, a leading cause of vision loss. "There has long been a question about whether maintaining a healthy lifestyle can delay or prevent the development of macular degeneration. The way that question has historically been answered has been by taking surveys of people, asking them what they are eating and how much exercise they are performing. That is basically the most sophisticated study that has been done. The problem with that is that people are notoriously bad self-reporters - and that can lead to conclusions that may or not be true. This study offers hard evidence from the lab for very first time."
Enticingly, the research found that the bar for receiving the benefits from exercise was relatively low - more exercise didn't mean more benefit. "Mice are like people in that they will perform a spectrum of exercise. As long as they had a wheel and ran on it, there was a benefit. The benefit that they obtained is saturated at low levels of exercise." An initial test comparing mice that voluntarily exercised versus those that did not found that exercise reduced the blood vessel overgrowth by 45%. A second test, to confirm the findings, found a reduction of 32%.
The scientists aren't certain exactly how exercise is preventing the blood vessel overgrowth. There could be a variety of factors at play, including increased blood flow to the eyes. "It is fairly well known that as people's eyes and vision deteriorate, their tendency to engage in physical activity also goes down. It can be a challenging thing to study in older people. How much of that is one causing the other? The next step is to look at how and why this happens, and to see if we can develop a pill or method that will give you the benefits of exercise without having to exercise."
Cortisol Declines in the Old, Causing Macrophages to Become More Inflammatory
Researchers here show that declining cortisol levels cause macrophage cells of the innate immune system to become more inflammatory with age. This contributes to the state of chronic inflammation in older individuals that accelerates the onset and progression of age-related disease. The aging immune system becomes overactive (inflammaging) and less capable (immunosenescence), and its chronic inflammation acts to disrupt tissue maintenance and cell behavior in numerous harmful ways. Loss of cortisol is only a proximate cause of chronic inflammation, however, and the present research says little of how this relates to deeper causes of aging. Nonetheless, it is one of many lines of research that indicate the importance of inflammation to the aging process.
A persistent state of inflammation can cause serious damage to our bodies. One consequence is that chronic inflammatory diseases, such as atherosclerosis or arthritis, are far more prevalent in older patients. What was uncertain up until now was what actually caused these inflammatory responses to flare up. Researchers have now provided some important insight: the inflammatory process is linked to the fact that the amount of cortisol generated in the body decreases as we get older.
Cortisol and its inactive form cortisone, commonly referred to as stress hormones, are released by the adrenal gland. The hormone cortisol acts as a biochemical signalling molecule and is involved in numerous metabolic processes in the body. Cortisol deficiency in the body leads to an inflammatory response. "The serum level of cortisol in the body is lower in the elderly. Moreover, macrophages, an important type of immune cells, can convert inactive cortisone to active cortisol, but this ability declines with increasing age. What we observe is what we could call "macroph-ageing" - the age-induced disruption of macrophage functions."
Macrophages are important cells within the immune system that use signalling molecules to control other immune cells. They play a critical role in determining the extent of our body's inflammatory response. However, macrophage function becomes impaired with increasing age. This can lead to an increase in the quantities of pro-inflammatory signalling molecules, which in turn drives the activity of other inflammatory cells of the body's immune system.
Researchers found that one particular protein is implicated in the malfunctioning of macrophages in the elderly. The protein is known as GILZ and its levels are regulated in part by cortisol. A lower cortisol level causes macrophages to produce less GILZ, which in turn means that the macrophages simply continue to release inflammatory signalling molecules. The team found that GILZ levels are indeed lower in older subjects. To find out whether that in itself was enough to cause an inflammatory response, researchers genetically deactivated the GILZ protein. The data confirmed that the macrophages were activated and there was a resulting increase in chronic inflammatory processes.
Why Do Older Mothers Produce Less Robust Offspring?
It is well understood that an older maternal age at birth results in offspring that are less robust, meaning a shorter life expectancy, lesser degrees of reproductive success, and so forth. The question asked here is how this effect can have persisted in the face of evolutionary competition: why do we not see organisms that can produce equally viable offspring at later ages? This is one slice of the broader evolutionary question of why aging happens at all, and why it is near universal in the animal kingdom. The present consensus on the evolution of aging, insofar as there is a consensus, is the antagonistic pleiotropy hypothesis. Selection pressure is stronger in younger individuals, leading to mechanisms and biological systems that are beneficial in youth but harmful in later life. This, of course, is entirely adequate to explain the observation that older mothers have less robust offspring; it is one narrow manifestation of aging.
In many species, survival and reproduction decrease with advancing age, a process known as "senescence." The evolution of senescence is a long-standing problem in life history theory and has been studied extensively in the laboratory, with mathematical models, and in the field. The evolution of senescence is explained by the age-specific patterns of the strength of selection, measured as selection gradients. Age-specific selection gradients on mortality and fertility decrease with age. Thus, traits expressed early in life have a larger impact on fitness than those expressed later. As a result, selection will favor traits that lead to negative effects on survival and fertility at older ages if there are even small beneficial effects in youth.
"Maternal effect senescence" is defined as the reduced success or quality of offspring with advancing age of the mother. Advanced maternal age has known negative effects on offspring health, lifespan, and fertility in humans and other species. In many taxa, including rotifers, Daphnia, Drosophila, and soil mites, offspring from older mothers have shorter lives, lower reproductive success, or both. Field studies of several species of mammals and birds have shown that offspring with older parents exhibit lower survival and recruitment and increased rates of senescence. In humans, advanced maternal age is associated with reduced lifespan and health. In Caenorhabditis elegans, Daphnia, and rotifers, advanced maternal age also increases offspring size, alters development time, and increases variability in gene expression.
Maternal effect senescence remains an interesting problem in life history evolution. Producing high-quality offspring that live long and prosper should, all else being equal, provide a selective advantage. Thus, the reduced quality of the offspring of old mothers demands an evolutionary explanation. We developed a more general multistate model that can incorporate maternal age effects on age-specific survival and fertility throughout the life cycle and with which we can easily calculate selection gradients on any of those rates as joint functions of age and maternal age.
We fit these models to data from individual-based culture experiments on the aquatic invertebrate, Brachionus manjavacas (Rotifera). By comparing models with and without maternal effects, we found that maternal effect senescence significantly reduces fitness for B. manjavacas and that this decrease arises primarily through reduced fertility, particularly at maternal ages corresponding to peak reproductive output. We also used the models to estimate selection gradients, which measure the strength of selection, in both high growth rate (laboratory) and two simulated low growth rate environments. In all environments, selection gradients on survival and fertility decrease with increasing age. They also decrease with increasing maternal age for late maternal ages, implying that maternal effect senescence can evolve through the same process as in the theory of the evolution of age-related senescence.
Ex Vivo Mitochondrial Transfer as a Way to Improve Stem Cell Therapy Outcomes
A sizable portion of the variable efficacy of first generation stem cell therapies as presently practiced may be due to a poor quality of cells following expansion in culture. Regardless of quality, near all such cells die shortly after transplantation. Few clinics and few approaches to cell therapy lead to lasting survival and engraftment of transplanted cells, and beneficial effects are largely mediated by the short period of signaling produced by these cells. A range of approaches have been taken in attempts to make transplanted cells more robust: methodological improvements in the process of obtaining and culturing cells for transplant; transplanting a scaffold material along with cells; providing cells with supporting signals or nutrients; engineering cells to produce proteins that will help in survival; culling senescent cells from the culture prior to transplantation. Adding to these, researchers here report on the use of mitochondrial transfer, taking advantage of a process that does occur naturally, in which cells take up mitochondria from the surrounding medium.
Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is considered a promising therapeutic approach for bone defect repair. However, during the transplantation procedure, the functions and viability of BMSCs may be impaired due to extended durations of in vitro culture, aging, and disease conditions of patients. Inspired by spontaneous intercellular mitochondria transfer that naturally occurs within injured tissues to rescue cellular or tissue function, we investigated whether artificial mitochondria transfer into pre-transplant BMSCs in vitro could improve cellular function and enhance their therapeutic effects on bone defect repair in situ.
Mitochondria were isolated from donor BMSCs and transferred into recipient BMSCs of the same batch and passage. Subsequently, changes in proliferative capacity and cell senescence were evaluated. After that, in vivo experiments were performed by transplanting mitochondria-recipient BMSCs into a rat cranial critical-size bone defect model. Micro CT scanning and histological analysis were conducted at 4 and 8 weeks after transplantation to evaluate osteogenesis in situ. Finally, in order to establish the correlation between cellular behavioral changes and aerobic metabolism, OXPHOS (oxidative phosphorylation) and ATP production were assessed and inhibition of aerobic respiration by oligomycin was performed.
Mitochondria-recipient BMSCs exhibited significantly enhanced proliferation and migration, and increased osteogenesis upon osteogenic induction. The in vivo results showed more new bone formation after transplantation of mitochondria-recipient BMSCs in situ. Increased OXPHOS activity and ATP production were observed, which upon inhibition by oligomycin attenuated the enhancement of proliferation, migration, and osteogenic differentiation induced by mitochondria transfer. Thus mitochondria transfer is a feasible technique to enhance BMSC function in vitro and promote bone defect repair in situ through the upregulation of aerobic metabolism.
Differences in Exosome MicroRNA Content Following Exercise in Sedentary versus Fit Older People
Researchers here note one example of the many differences that exist between good and poor fitness in older people. The response to exercise is materially different between fit and sedentary individuals at all levels of cellular metabolism. The microRNA contents of exosomes, a class of extracellular vesicle that carries signals between cells, is one of these countless differences. It is possible that this sort of exploratory study may lead to therapies based on delivery of manufactured exosomes containing specific microRNAs, and there is certainly a growing industry of companies working on exosome manufacture to support such an effort.
Exercise has multi-systemic benefits and attenuates the physiological impairments associated with aging. Emerging evidence suggests that circulating exosomes mediate some of the beneficial effects of exercise via the transfer of microRNAs between tissues. However, the impact of regular exercise and acute exercise on circulating exosomal microRNAs (exomiRs) in older populations remains unknown. In the present study, we analyzed circulating exomiR expression in endurance-trained elderly men (n = 5) and age-matched sedentary males (n = 5) at baseline (Pre), immediately after a forty minute bout of aerobic exercise on a cycle ergometer (Post), and three hours after this acute exercise (3hPost).
Following the isolation and enrichment of exosomes from plasma, exosome-enriched preparations were characterized and exomiR levels were determined by sequencing. The effect of regular exercise on circulating exomiRs was assessed by comparing the baseline expression levels in the trained and sedentary groups. The effect of acute exercise was determined by comparing baseline and post-training expression levels in each group. Regular exercise resulted in significantly increased baseline expression of three exomiRs (miR-486-5p, miR-215-5p, miR-941) and decreased expression of one exomiR (miR-151b). Acute exercise altered circulating exomiR expression in both groups. However, exomiRs regulated by acute exercise in the trained group (7 miRNAs at Post and 8 at 3hPost) were distinct from those in the sedentary group (9 at Post and 4 at 3hPost).
Pathway analysis prediction and reported target validation experiments revealed that the majority of exercise-regulated exomiRs are targeting genes that are related to IGF-1 signaling, a pathway involved in exercise-induced muscle and cardiac hypertrophy. The immediately post-acute exercise exomiR signature in the trained group correlates with activation of IGF-1 signaling, whereas in the sedentary group it is associated with inhibition of IGF-1 signaling. While further validation is needed, including measurements of IGF-1/IGF-1 signaling in blood or skeletal muscle, our results suggest that training status may counteract age-related anabolic resistance by modulating circulating exomiR profiles both at baseline and in response to acute exercise.
Stem Cell Exhaustion in the Aging Lung
Stem cell activity declines with age throughout the body. In some cases this is because stem cells become less active in response to changes in the signaling environment. In other cases, the cells are damaged or the populations greatly reduced. The consequence of this decline is that fewer daughter somatic cells are produced to make up losses, repair damage, and maintain tissue function. A slow decline into organ dysfunction results, contributing to the onset of age-related disease, disability, and mortality. Finding ways to reverse this process is a very important component of of the broader field of rejuvenation research.
Tissue stem cell exhaustion is a key hallmark of aging, and in this study, we characterised its manifestation in the distal lung. We compared the lungs of 3- and 22-month old mice. We examined the gross morphological changes in these lungs, the density and function of epithelial progenitor populations and the epithelial gene expression profile. Bronchioles became smaller in their cross-sectional area and diameter. We found that bronchiolar cell density remained stable with aging, but inferred rates of progenitor cell self-renewal and differentiation were reduced, indicative of an overall slowdown in cellular turnover.
Alveolar Type II progenitor cell density and self-renewal were maintained per unit tissue area with aging, but rates of inferred differentiation into Type I cells, and indeed overall density of Type I cells was reduced. Microarray analysis revealed age-related changes in multiple genes, including some with roles in proliferation and differentiation, and in IGF and TGFβ signalling pathways. By characterising how lung stem cell dynamics change with aging, this study will elucidate how they contribute to age-related loss of pulmonary function, and pathogenesis of common age-related pulmonary diseases.