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- 30% to 40% of Dementia Might be Avoided via Lifestyle Choices
- Telomerase Gene Therapy May Treat Fibrosis via a Reduced Burden of Cellular Senescence
- Reducing LDL Cholesterol is the Wrong Target for Cardiovascular Disease
- Reviewing Associations Between Physical Activity and Loss of Average Telomere Length with Age
- Reviewing the Mechanisms of Longevity in Long-Lived Bats
- Arguing for DNA Methylation Changes to be a Contributing Cause of Aging
- IGF-1R Inhibition Reduces Neuroinflammation in an Alzheimer’s Mouse Model
- The Gut Microbiome Changes Shortly Before Death in Centenarians
- Overexpression of VRK-1 Extends Life Span in Nematode Worms
- A Fisetin Variant, CMS121, Slows Disease Progress in an Alzheimer’s Mouse Model
- Considering the Use of Lasers to Break Down Harmful Protein Aggregates
- Should Rapamycin be Prescribed Ubiquitously as an Anti-Aging Supplement?
- Exercise May Aid in Resisting Frailty and Cognitive Decline in Part via Effects on the Gut Microbiome
- Mitochondrial Dysfunction in Monocytes of the Innate Immune System Contributes to Inflammaging
- Astaxanthin as a Geroprotective Compound
30% to 40% of Dementia Might be Avoided via Lifestyle Choices
Today’s open access research materials present a statistical exercise that uses broad epidemiological data to determine the impact of individual lifestyle choices and environmental factors to the incidence of dementia. The results are not declaring that, say, particulate air pollution is responsible for 2% of dementias. Rather if the statistics point out that particulate air pollution is associated with 2% of cases, smoking with 5%, and hearing loss with 8%, then one starts to see priorities in the choices that people should be making to better manage their health over the long term.
Summing all of the impacts together – to see a 30-40% contribution of lifestyle and environment to incidence of dementia – also provides an assessment of the degree to which dementia is a lifestyle disease. To which it is avoidable with sensible choices regarding health and surrounding environment. Alzheimer’s disease in particular involves a number of mechanisms that look suspiciously like those involved in type 2 diabetes, a condition that is near entirely a lifestyle issue resulting from excess fat tissue. Nonetheless, Alzheimer’s disease and other dementias are clearly not determined by obesity to the same degree. The risk spreads out over choices and influences that touch on chronic inflammation (fat, smoking, air pollution), cognitive reserve (education), physical damage to brain tissue and surrounding channels for cerebrospinal fluid drainage (hypertension, head injury). It is a matter of many smaller contributions that cause harm through a range of quite different mechanisms.
While senolytic drugs that remove senescent cells in the brain will probably make a sizable difference to dementia incidence, via greatly reducing inflammation in brain tissue, it remains the case that comparatively little else can be done at present other than slowing the decline through better life-long health. More and better regenerative therapies, and more and better therapies that target the underlying molecular damage of brain aging are needed.
Dementia prevention, intervention, and care: 2020 report of the Lancet Commission
Overall, a growing body of evidence supports the nine potentially modifiable risk factors for dementia modelled by the 2017 Lancet Commission on dementia prevention, intervention, and care: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and low social contact. We now add three more risk factors for dementia with newer, convincing evidence. These factors are excessive alcohol consumption, traumatic brain injury, and air pollution. We have completed new reviews and meta-analyses and incorporated these into an updated 12 risk factor life-course model of dementia prevention. Together the 12 modifiable risk factors account for around 40% of worldwide dementias, which consequently could theoretically be prevented or delayed. The potential for prevention is high and might be higher in low-income and middle-income countries (LMIC) where more dementias occur.
The number of people with dementia is rising. Predictions about future trends in dementia prevalence vary depending on the underlying assumptions and geographical region, but generally suggest substantial increases in overall prevalence related to an ageing population. For example, according to the Global Burden of Diseases, Injuries, and Risk Factors Study, the global age-standardised prevalence of dementia between 1990 and 2016 was relatively stable, but with an ageing and bigger population the number of people with dementia has more than doubled since 1990.
However, in many high income countries (HIC) such as the USA, the UK, and France, age-specific incidence rates are lower in more recent cohorts compared with cohorts from previous decades collected using similar methods and target populations and the age-specific incidence of dementia appears to decrease. All-cause dementia incidence is lower in people born more recently, probably due to educational, socio-economic, health care, and lifestyle changes. However, in these countries increasing obesity and diabetes and declining physical activity might reverse this trajectory. In contrast, age-specific dementia prevalence in Japan, South Korea, Hong Kong, and Taiwan looks as if it is increasing, as is Alzheimer’s in LMIC, although whether diagnostic methods are always the same in comparison studies is unclear.
Cognitive reserve is a concept accounting for the difference between an individual’s clinical picture and their neuropathology. It is divided into neurobiological brain reserve (eg, numbers of neurons and synapses at a given timepoint), brain maintenance (as neurobiological capital at any timepoint, based on genetics or lifestyle reducing brain changes and pathology development over time) and cognitive reserve as adaptability enabling preservation of cognition or everyday functioning in spite of brain pathology. Early-life factors, such as less education, affect the resulting cognitive reserve. Midlife and old-age risk factors influence age-related cognitive decline and triggering of neuropathological developments. Consistent with the hypothesis of cognitive reserve is that older women are more likely to develop dementia than men of the same age, probably partly because on average older women have had less education than older men. Cognitive reserve mechanisms might include preserved metabolism or increased connectivity in temporal and frontal brain areas.
Risk factors in early life (education), midlife (hypertension, obesity, hearing loss, traumatic brain injury, and alcohol misuse) and later life (smoking, depression, physical inactivity, social isolation, diabetes, and air pollution) can contribute to increased dementia risk. Good evidence exists for all these risk factors although some late-life factors, such as depression, possibly have a bidirectional impact and are also part of the dementia prodrome. Our new life-course model and evidence synthesis has paramount worldwide policy implications. It is never too early and never too late in the life course for dementia prevention. Early-life (younger than 45 years) risks, such as less education, affect cognitive reserve; midlife (45-65 years), and later-life (older than 65 years) risk factors influence reserve and triggering of neuropathological developments.
Telomerase Gene Therapy May Treat Fibrosis via a Reduced Burden of Cellular Senescence
A number of research groups are quite enthusiastic about the prospects for telomerase gene therapy as a treatment for aging and numerous age-related diseases. This is based on more than a decade of work in mice, showing extended life spans and improved metabolism. Over the past few years, reversal of fibrosis via telomerase gene therapy has been demonstrated in mice. The evidence for this to be an approach worth bringing to the clinic continues to accumulate. Fibrosis is a disruption of tissue maintenance, associated with chronic inflammation, in which an inappropriate deposition of scar-like collagen takes place, degrading normal tissue structure and function. Today’s research materials are the latest on this topic, in which scientists dig deeper into the mechanisms by which telomerase upregulation might be acting on fibrosis in the lung.
The primary function of telomerase is to extend telomeres, caps of repeated DNA at the ends of chromosomes. Telomere length shortens with every cell division, but only stem cells normally express telomerase and thus have the capability to maintain long telomeres. The vast majority of somatic cells in the body lose their telomere length until hitting the Hayflick limit, at which point their shortened telomeres trigger cell death or cellular senescence. All tissues are in a state of turnover, losing cells to the Hayflick limit, while replacements with long telomeres are generated by stem cells.
Telomerase upregulation might produce benefits in a number of ways. Firstly, if all cells express telomerase, then there will tend to be more functional cells in any given tissue, postponing age-related declines in function that occur due to a slowing of stem cell activity. A concern here is that this will allow damaged cells to function for longer, and thus raise cancer risk. That raised risk doesn’t occur in mice with upregulated telomerase, possibly because immune system function is improved by telomerase gene therapy in the same way as other tissue function, and improved cancer suppression by immune cells outweighs the increased risk due to lengthening the telomeres of damaged and potentially cancerous cells. Whether or not the same balance of factors will occur in humans is still to be determined.
Secondly, telomerase upregulation may reduce the burden of senescent cells in tissues, both by preventing cells from replicative senescence, and by improving the operation of mechanisms that clear senescent cells. Senescent cells are important in aging, as demonstrated by the extension of life and reversal of age-related disease produced in mice via senolytic therapies that selectively remove these errant cells. Interestingly, senescent cells are strongly implicated in the progression of fibrosis, and their removal has been shown to reverse the condition in mice. In the research noted here, telomerase gene therapy reduces measures of senescence in fibrotic lungs. It is entirely plausible that this is the primary mechanism by which increased telomerase activity acts to reverse fibrosis.
Researchers pave the way for a future gene therapy to reverse pulmonary fibrosis associated with ageing
Idiopathic pulmonary fibrosis is a potentially lethal disease for which there is currently no cure and that is associated with certain mutations or advanced age. Resesarchers had previously developed an effective therapy for mice with fibrosis caused by genetic defects. Now they show that the same therapy can successfully be used to treat mice with age-related fibrosis. The treatment tested in mice is a gene therapy that activates the production of telomerase in the body. Telomerase is an enzyme that repairs the telomeres at the end of chromosomes.
The new study describes the effects of ageing on lung tissue in detail. One such effect is that alveolar type II cells stop doing their job. In addition to regenerating tissue, these cells produce and release a lipid-protein complex called pulmonary surfactant that facilitates the mechanical work done by the lungs. “Lung tissue must expand when we breathe in, six to ten times per minute, which means a great deal of physical effort. Pulmonary surfactant plays an important role in lubricating lung tissue, retaining its elasticity, and reducing the amount of work required to expand and contract it. If type II pneumocytes fail to regenerate, the surfactant is not produced, which results in lung stiffness and fibrosis.”
In 2018, researchers developed a gene therapy that reversed pulmonary fibrosis in mice lacking the telomerase gene. This therapy was based on activating telomerase expression temporarily. A virus used as a telomerase gene carrier was injected intravenously into the mice. The effect – alveolar type II cells with long telomeres – was temporary, but lung tissue regeneration was successfully induced. The same therapy was now used in aging mice. And it worked in them too. “The telomerase-activating gene therapy prevented the development of fibrosis in all mice, including the ones without genetic alterations that only underwent physiological ageing.”
Telomerase treatment prevents lung profibrotic pathologies associated with physiological aging
We determined the impact of AAV9-Tert gene therapy in rescuing DNA damage, apoptosis, and senescence in Tert+/+ and Tert-/- lungs treated with either AAV9-Tert or AAV9-null virus particles. We found that both Tert+/+ and Tert-/- mice treated with AAV9-Tert showed significantly decreased numbers of γ-H2AX-positive cells in the lung parenchyma compared with the corresponding cohorts treated with the null vector, indicating decreased DNA damage upon telomerase treatment. Similarly, we detected significantly decreased numbers of activated caspase3-positive cells in the alveolar parenchyma of both Tert+/+ and Tert-/- lungs treated with AAV9-Tert compared with those treated with the null vector. Interestingly, increased senescence as detected by p16-positive cells specifically in the case of aveolar macrophages was also rescued in both Tert+/+ and Tert-/- lungs treated with AAV9-Tert compared with those treated with the null vector.
Finally, by performing double immunostainings with the proliferation marker Ki67 and the specific markers for alveolar type II cells, club cells, and aveolar macrophages, we observed that proliferation of alveolar type II cells, club cells, and aveolar macrophages was significantly increased in both Tert+/+ and Tert-/- lungs treated with AAV9-Tert compared with those treated with the null vector. Interestingly, the number of SOX2-positive differentiating club cells was also significantly reduced in Tert+/+ and Tert-/- lungs upon telomerase gene therapy.
Finally, to address whether treatment with telomerase gene therapy also prevented expression of proinflammatory and anti-inflammatory markers, we determined mRNA expression of Tnf, Il1b, Il6, Il4, Il10, and Il13 in total lung extracts from Tert+/+ and Tert-/- mice. We observed significantly decreased expression of these markers in both Tert+/+ andTert-/- mice treated with AAV9-Tert compared with those treated with the null vector.
Reducing LDL Cholesterol is the Wrong Target for Cardiovascular Disease
When people say “cardiovascular disease” in the context of blood cholesterol, they mean atherosclerosis. This is the name given to the build up of fatty deposits that narrow and weaken blood vessels, leading to heart failure and ultimately some form of disabling or fatal rupture – a stroke or heart attack. The primary approach to treatment is the use of lifestyle choices and drugs such as statins to lower cholesterol carried by LDL particles in the blood. Unfortunately, the evidence strongly suggests that this is the wrong approach, in that the benefits are small and unreliable.
Atherosclerosis does occur more readily with very high levels of LDL cholesterol, as illustrated by the early onset of the condition in patients with genetic disorders such as homozygous familial hypercholesterolemia, in which blood cholesterol can be as high as ten times normal. Yet reducing LDL cholesterol levels, even to as much as ten times lower than normal, does very little for patients with established atherosclerotic lesions. One has to look at the mechanisms of the disease in more detail to (a) see why this is the case, and (b) identify which classes of therapy should be attempted instead.
Atherosclerosis is essentially a consequence of the failure of a process called reverse cholesterol transport. When cholesterol becomes stuck in excessive amounts in blood vessel walls, macrophage cells of the innate immune system are called to the site. The macrophages ingest cholesterol and then hand it off to HDL particles. The HDL cholesterol is then carried to the liver to be excreted. This all works just fine in young people. Older people, however, exhibit growing levels of oxidized cholesterols such as the toxic 7-ketocholesterol. Even small amounts of these oxidized cholesterols disrupt macrophage function in ways that are otherwise only achievable through very sizable amounts of cholesterol. The macrophages become inflammatory, cease their work, become loaded down with cholesterol, and die. An atherosclerotic lesion is essentially a self-sustaining macrophage graveyard that will keep pulling in and destroying ever more cells, growing larger as it does so.
The right point of intervention in atherosclerosis is therefore macrophage function. Make macrophages resistant to oxidative cholesterol and cholesterol overload, as Repair Biotechnologies is doing. Or remove oxidized cholesterols from the body, as Underdog Pharmaceuticals is doing. The crucial goal is to allow macrophages to operate normally in the toxic environment of the atherosclerotic lesion; given enough time, it is in principle possible for these cells to dismantle even advanced and sizable lesions. That they do not normally do this is because of oxidized cholesterols or sheer amount of cholesterol, not any other inherent limit.
Doubt cast on wisdom of targeting ‘bad’ cholesterol to curb heart disease risk
Setting targets for ‘bad’ (LDL) cholesterol levels to ward off heart disease and death in those at risk might seem intuitive, but decades of research have failed to show any consistent benefit for this approach, reveals a new analysis. If anything, it is failing to identify many of those at high risk while most likely including those at low risk, who don’t need treatment, say the researchers, who call into question the validity of this strategy.
Cholesterol-lowering drugs are now prescribed to millions of people around the world in line with clinical guidelines. Those with poor cardiovascular health; those with LDL cholesterol levels of 190 mg/dl or higher; adults with diabetes; and those whose estimated risk is 7.5% or more over the next 10 years, based on various contributory factors, such as age and family history, are all considered to be at moderate to high risk of future cardiovascular disease. But although lowering LDL cholesterol is an established part of preventive treatment, and backed up by a substantial body of evidence, the approach has never been properly validated, say the researchers.
Hit or miss: the new cholesterol targets
This analysis highlights the discordance between a well-researched clinical guideline written by experts and empirical evidence gleaned from dozens of clinical trials of cholesterol reduction. It further underscores the ongoing debate about lowering cholesterol in general and the use of statins in particular. In this analysis over three-quarters of the cholesterol lowering trials reported no mortality benefit and nearly half reported no cardiovascular benefit at all.
The widely held theory that there is a linear relationship between the degree of LDL-C reduction and the degree of cardiovascular risk reduction is undermined by the fact that some randomized controlled trials with very modest reductions of LDL-C reported cardiovascular benefits while others with much greater degrees of LDL-C reduction did not. This lack of exposure-response relationship suggests there is no correlation between the percent reduction in LDL-C and the absolute risk reduction in cardiovascular events.
Moreover, consider that the Minnesota Coronary Experiment, a 4-year long randomized controlled trial of a low-fat diet involving 9423 subjects, actually reported an increase in mortality and cardiovascular events despite a 13% reduction in total cholesterol. What is clear is the lack of clarity of these issues. In most fields of science the existence of contradictory evidence usually leads to a paradigm shift or modification of the theory in question, but in this case the contradictory evidence has been largely ignored simply because it doesn’t fit the prevailing paradigm.
Reviewing Associations Between Physical Activity and Loss of Average Telomere Length with Age
Telomeres are repeated DNA sequences at the ends of chromosomes. With each cell division a little telomere length is lost, and this is an important part of the countdown mechanism that limits replication of somatic cells. Somatic cells with short telomeres become senescent or self-destruct. Stem cells, on the other hand, use telomerase to lengthen their telomeres, and thus produce daughter somatic cells with long telomeres throughout a lifetime. This two-tier system of privileged stem cells and limited somatic cells, present in near all animals, keeps the risk of cancer low enough for evolutionary success, while still allowing for tissue maintenance and cell turnover.
Average telomere length in tissues declines with age, and this is largely a function of loss of stem cell activity. There are fewer replacement cells with long telomeres. Telomere length is usually measured in immune cells in a blood sample, however, and here there are many more factors at work to muddy the waters. Immune cells will replicate at quite different rates from day to day, depending circumstances ranging from stress to infection. In human studies, telomere length only exhibits associations with aging – or with interventions known to modestly slow aging – in the statistics of large groups. Even then many studies fail to find a good correlation with diet, exercise, and the like. Thus for any given individual there usually isn’t much to learn from a measure of telomere length, or a change in that measure over time.
Physical activity, a modulator of aging through effects on telomere biology
Telomere length (TL) varies greatly between species. At birth, every human individual has a specific TL that ranges between 5 to 15 kb. Throughout life telomeres shorten continuously with a rate between 20-50 bp due to the end-replication phenomenon, oxidative stress, and other modulating factors. However, telomere shortening rates and consequently also average TL vary amongst different tissue types, which is at least partly explained by tissue-specific proliferation rates. In dividing cells, the end replication problem is an important driver of telomere shortening that can be modified by other factors, such as oxidative stress or inflammation. In postmitotic cells instead oxidative stress can directly damage telomeric DNA and drive cells into senescence.
The TL of peripheral blood leucocytes (LTL) has gained substantial interest as a potential marker of biological age. Mean LTL in adults is approximately 11 kb and declines with an annual rate of 30-35 bp. Telomere attrition is most pronounced during the first two years of life, which are characterized by rapid somatic growth. The shortening of telomeres is not a unidirectional process since the reverse-transcriptase telomerase is capable of adding to telomeric ends. However, most somatic cells do not express telomerase. Detectable levels of telomerase activity can typically be found in germ line and embryonic stem cells, immune cells, and in cancer cells.
Regular exercise is a well-established approach to reduce the risk of morbidity and premature mortality. Prospective cohort studies demonstrate that men and women who regularly exercise, have a 30% lower all-cause mortality risk than sedentary individuals. In the older persons the beneficial effects of regular physical activity (above 200 minutes a day) are even more pronounced reaching up to 40% or more mortality risk reduction. Besides a substantial reduction of mortality, regular exercise also reduces the incidence and progression of coronary heart disease, hypertension, stroke, diabetes, metabolic syndrome, colon cancer, breast cancer, and depression. Despite the existence of robust evidence for multiple health benefits of regular exercise, the underlying mechanisms are insufficiently understood. General key mechanisms that drive the process of aging include the accumulation of genetic damage, epigenetic modifications, and shortening of telomeres. It has been speculated that exercise can help preserve TL through the induction of telomerase.
Despite robust evidence from cross-sectional and prospective intervention studies, not all previously published analyses support a relationship between exercise and telomere biology, however. For example, in a cross-sectional and longitudinal analyses of 582 older adults, researchers found no consistent relationship between physical activity and LTL.
Telomere research has gained much attention in the previous decade for its potential use and promise as a future therapeutic target, disease management, and measurement of genomic aging. Interventions, such as physical activity, that target the deleterious processes of aging have concomitantly created interest in the area of lifestyle and aging related research. Largely, the available physical activity data do not exclude that an association between regular exercise and TL exists. However, to date, the observed results from human studies are skewed largely by associations and observational or cross-sectional data. In light of the limited data, available evidence suggests altogether, that regular, and consistent physical activity over an extended period of time may assist with preservation of telomeres and cellular aging. Nevertheless, conflicting and a lack of consistent findings from the existing evidence, and particularly from the few available mechanistic studies means there is much more to explore and understand, prior to measurements such as TL will be adopted clinically.
Reviewing the Mechanisms of Longevity in Long-Lived Bats
Today’s open access research is a good companion piece to a recent paper that investigates biochemical differences between long-lived and short-lived bats. Bats are renowned for, firstly, an exceptional resistance to classes of virus that are fatal to other mammals, allowing bat populations to act as reservoirs for potentially dangerous pathogens, and secondly for an exceptional longevity in comparison to other mammalian species of a similar size. In mammals, species longevity tends to scale up with size, with a few notable and well-studied long-lived exceptions such as naked mole-rats, humans, and some bats.
In terms of asking why longevity occurs in these species, for naked mole-rats (and near relative species) it may be a side-effect of tolerating oxygen-poor underground environments, providing greater resistance to mechanisms of cell damage that also occur with age. For we humans, the grandmother hypothesis suggests that our culture and intelligence allows older individuals to contribute to the fitness of descendants in ways that other primates do not, and thus there is selection pressure for a longer, slower decline after menopause. As for bats (and birds, which are also, as a rule, long-lived for their size) the high metabolic demands of flight are thought to provide the side-effect of greater longevity for similar reasons to the longevity of naked mole rats, a resistance to cellular damage that occurs with both exertion and aging.
Finding out whether or not these proposals are in fact the case requires a deep analysis of cellular biochemistry, comparing long-lived and short-lived mammals. That analysis is very much a work in progress, providing a great many potential mechanisms to consider and compare, while the present consensus on what is important and what is relevant remains subject to being overturned at short notice. Today’s open access paper is a good review of what is known of bat longevity, with the added bonus of a discussion of viral resistance in these species, which may well turn out to be relevant to the question of life span, given the interactions between infection, inflammation, and aging.
The World Goes Bats: Living Longer and Tolerating Viruses
One of the most amazing properties of bats is their longevity. Many bat species such as little brown bat, Brandt’s bat, mouse-eared bat, and Indian flying fox have maximum lifespans of 30-40 years. Other bat species have maximum lifespans around 20 years, which is still very long for species of this size. Extreme longevity has arisen at least four separate times during bat speciation. These findings suggest that long lifespan is no accident; it either arose because long lifespan has fitness benefits for bats or because some other phenotype is selected that also precipitates longevity, one of which being a dampened immune response.
The reasons behind the long lifespan of bats remain debated, with scientists developing hypotheses based either on evolutionary life history or molecular studies testing known longevity pathways. Bats have several features that would favor selection for low mortality rates, including small litters, the capacity of flight (which permits escape from predators), and (in many species) the ability to hibernate, or enter into a low-energy torpor state. Torpor is linked to longevity in bats and other species and may protect the animal from bouts of starvation and/or promote homeostatic maintenance during periods of low metabolic rate. Consistent with a beneficial role for hibernation, other species that can enter hibernation, such as gray mouse lemurs and 13-lined squirrels, have longer lifespan than mice of similar size.
Genomic studies have pointed to some longevity clues. For instance, the genome of the Brandt’s bat and several other species has a mutation in the growth hormone receptor gene that may interfere with transmembrane domain function. Growth hormone receptor loss of function mutations are associated with protection from diabetes and cancer in humans and long lifespan in mice. Indeed, bats have physiologic (e.g., pancreatic structure) and transcriptomic changes that resemble growth hormone receptor knockout mice. There are also intriguing changes in the transmembrane region of the IGF1 receptor, which is associated with longevity in a range of model organisms and in centenarians. Both of these hormonal signaling pathways are intimately linked to nutrient signaling, one of the most robust pillars of aging.
Genome maintenance is an important longevity assurance mechanism and another recognized pillar of aging. In an 8-year longitudinal study of blood samples from free-living greater mouse-eared bats (Myotis myotis), it was reported that DNA repair and DNA damage signaling pathways are maintained throughout lifespan, consistent with the low levels of cancer in bat species. Among DNA repair pathways, DNA double-strand break repair shows the strongest correlation with longevity. Remarkably several DNA double-strand break repair genes were shown to be under positive selection in two species of bats. Interestingly, some of these DNA repair genes, such as DNA-PK and Rad50, also function as DNA sensors in innate immune response. Hence, the genetic changes that evolved in bats may modulate both processes simultaneously and the innate immune response may be an evolutionary driver of positive selection.
Mitochondrial dysfunction is a feature of aging across the evolutionary spectrum and another highly supported pillar of aging. Energetic demands associated with flight in bats require enhanced mitochondrial respiratory metabolism, which is expected to generate excess oxidative damage. To counteract this damage, bats have evolved more efficient mitochondria, producing less H2O2 per unit oxygen consumed. Bat fibroblasts have also been shown to have lower levels of oxidative damage to proteins and to be resistant to acute oxidative stress. To help maintain proteostasis upon oxidative stress, bats express major heat shock proteins at higher levels. This may simultaneously permit bats to endure high temperatures with flight and maintain protein homeostasis with age. Bats also exhibit enhanced autophagy activity with advancing age, suggesting that their cells are better able to clear damaged proteins and organelles. Increased mitochondrial oxidative stress would also be expected to generate mitochondrial DNA alterations, or heteroplasmy. However, oxidative lesions in M. myotis are found only at low rates in an age-independent manner, suggesting better repair or removal of damaged mitochondria.
As they age, bats avoid upregulation of genes involved in chronic inflammation, which is typically not observed in mammals. This likely results from the multitude of mechanisms that evolved to suppress inflammation due to viral infections. Microbiome studies indicate that Myotis myotis may have stable microbiome composition that does not change over time in contrast to mice and humans, where the microbiome undergoes significant changes with age. As aging-related gut dysbiosis triggers inflammation, the ability of bats to maintain stable microbiome may contribute to the lack of age-related inflammation, or by contrast, low levels of inflammation may promote a more stable microbiome.
One major unanswered question is the extent to which cell senescence occurs with age in bats. Since cell senescence may be a major driver of chronic inflammation during mammalian aging, it will be important to determine whether cell senescence, another pillar, is altered with age in bat species. In-depth studies are needed to address this question in vivo and in cell culture. Among other hallmarks of aging, telomere attrition has been addressed to a limited extent, with mixed results. The shorter-lived bat species, Rhinolophus ferrumequinum and Miniopterus schreibersii, do exhibit telomere shortening, but no evidence was found in the longest-lived species, Myotis myotis. This bat apparently does not express telomerase but exhibits differential expression of genes involved in telomere maintenance and the alternative lengthening of telomeres (ALT) pathway.
A majority of the mechanisms that have evolved to protect bats from viruses likely contribute to their longevity. Bats evolved multiple strategies to combat inflammation, such as dampened NLRP3 inflammasome activity. Inflammation has emerged as a driver of multiple age-related pathologies, including cardiovascular diseases, cancer, Alzheimer’s disease, and diabetes. This led to the concept of inflammaging, defined as the long-term result of the chronic physiological stimulation of the innate immune system, which becomes damaging during aging. Factors that trigger inflammaging include viruses, microbiome bacteria, senescent cells, and self-products of cellular damage such as debris containing cellular DNA and proteins. Reducing inflammation due to any of these factors can be beneficial for longevity; however, bat evolution seems to have attenuated mechanisms of cytoplasmic DNA sensing specifically.
Remarkably, bats are unique in their ability to tolerate DNA transposable elements. DNA transposons move in the genome via a cut-and-paste mechanism involving DNA intermediates. Such transposons are found in invertebrates but are generally inactivated and fossilized in the genomes of mammals. Only the vespertilionid family of bats is known to harbor significant levels of active DNA transposable elements. This bat family includes genus Myotis, which contains the longest-lived bats, which suggests that these animals are exceptionally healthy. The ability to tolerate active DNA transposons is likely linked to dampened cytoplasmic DNA sensing.
In the continuing arms race against pathogens, evolutionary fitness requires a functional immune system. However, a highly active immune system may increase fitness in young age but limit longevity. Why did bat evolution result in adjusted immune system functions in a way that favors longevity? We speculate that bats’ exceptionally high exposure to viral pathogens forced them to develop ways to co-exist with viruses rather than to fight them. Bats are unique among mammals in the size and density of their colonies, and in their ability to fly long distances, a trait that further increases pathogen exposure. Modern humans living in large metropolises and enjoying air travel may be coming close to the bat level of viral exposure. However, humans have only been enjoying this lifestyle for less than 100 years, while bats evolved 60-70 million years ago.
Arguing for DNA Methylation Changes to be a Contributing Cause of Aging
Contributing mechanisms of aging form an interconnected network of cause and consequence. For most such mechanisms there is considerable debate over relative importance to the manifestations of aging, as well as over whether a mechanism is upstream or downstream of its peers. The step by step “A causes B causes C causes D” view of aging and age-related disease is very unclear in the middle reaches of the chain of cause and effect, despite a good list of first causes and a growing understanding of proximate causes for many age-related conditions. Progress is slow, as no biochemical mechanism exists in isolation, and it is a challenge to pick apart the complexities of cellular metabolism to find the important relationships.
Thus for DNA methylation, epigenetic changes that alter expression of proteins, at the high level one can argue that this is downstream of forms of damage and dysfunction, a response on the part of cells. One can also argue that some of these changes are harmful and cause further issues. Connecting DNA methylation to causes and consequences is an enormous undertaking, given the number of methylation sites that are now connected to aging as a result of work on epigenetic clocks. Nonetheless, some inroads are being made.
During aging, predefined genes constantly undergo epigenetic modifications and exhibit altered expression in response to internal and external environmental stress. Changes in DNA methylation may occur hundreds of times over the lifespan of an individual in the form of a fully adaptive response. However, in some cases, this methylation acts as a switch for the acceleration of pathological aging, resulting in negative consequences. Thus, global fluctuations in DNA methylation are not only a consequence but also a cause of aging. Understanding the biological mechanisms underlying the observed associations may reveal novel targets for reversing aging-related phenotypes and ultimately prolonging lifespan.
Evidence has emerged showing that decreased autophagic activity is involved in DNA methylation. DNA methylation inhibits autophagy processes in two ways, one of which is the direct modification and silencing of autophagy-related genes by DNA methyltransferases. The promoter regions of Atg5 and LC3 are hypermethylated in aged mice, which suppresses gene expression and disrupts the completion of autophagosomes. Whole-body overexpression of Atg5 results in antiaging phenotypes, extending the median lifespan of mice by 17.2%. Furthermore, researchers have recently shown that DNA methylation inhibitors can rescue phenotypic changes associated with aging by reactivating autophagy-related genes.
Identification of the target genes modified by DNA methylation-related regulatory elements in aging individuals is highly informative to figure out the hormone-like effectors and signal pathways that mediate these alterations as well as related diseases. The interaction among epigenetic regulators during aging should also be highly valued. Further studies should focus on the cross-talk among these epigenetic regulators, such as DNA methylation, RNA methylation, histone methylation, and noncoding RNAs, which will aid in providing a full picture of epigenetics and aging. The results of such studies may pave the way for antiaging interventions as well as treatments for related diseases, enabling human life extension.
IGF-1R Inhibition Reduces Neuroinflammation in an Alzheimer’s Mouse Model
Chronic inflammation in brain tissue is an important component of the progression of neurodegenerative conditions such as Alzheimer’s disease. It is important enough that some researchers propose inflammation resulting from persistent infection and cellular senescence to be the primary mechanism in Alzheimer’s disease, and the characteristic accumulation of amyloid-β deposits only a side-effect. Given the failure to achieve meaningful benefits in patients through removal of amyloid-β, researchers are turning their eyes towards ways to suppress inflammatory signaling in the brain. Removal of senescent cells, the source of a great deal of that inflammatory signaling, is one promising avenue, but other efforts focus on interference in specific signaling pathways, as is the case here.
Extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles are Alzheimer’s disease (AD) pathological features hypothesized to lead to neuronal death and cognitive dysfunction. Since aging is the main risk factor for AD, slowing down this process may delay disease onset or progression. The growth hormone (GH)/insulin-like growth factor (IGF-1) signaling pathway is hypothesized to be one of the primary pathways regulating lifespan in general. Partial inactivation of the IGF-1 receptor (IGF-1R) gene or insulin-like signaling extends longevity and postpones age-related dysfunction in nematodes, flies, and rodents.
The role of IGF-1 in regulating age-associated AD remains unclear. For instance, lower serum IGF-1 levels correlate with increased cognitive decline and risk of AD. Also, patients with familial AD demonstrate lower levels of circulating IGF-1 compared to controls. An ex vivo study revealed IGF-1 resistance along with insulin resistance through the PI3K pathway in AD patient brains. Finally, IGF-1 treatment diminished Aβ accumulation by improving its transportation out of the brains of AD mouse models while IGF-1R inhibition aggravated both behavioral and pathological AD symptoms in mice. On the other hand, the administration of a potent inducer of circulating IGF-1 levels failed to delay AD progression in a randomized trial. Also, acute or chronic delivery of IGF-1 exerted no beneficial effect on AD pathological hallmarks in rodent models in vivo. Moreover, high levels of serum IGF-1 were detected in individuals diagnosed with AD or other forms of dementia in one study.
Presumably, this dichotomy of effects is, in part, mediated through the effects of IGF-1 on its receptor. The IGF-1R and the insulin receptor (IR) are homologous tyrosine kinase proteins with remarkably different functions. In our previous work, AβPP/PS1 transgenic mice, which express human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1), demonstrated a decrease in brain IGF-1 levels when they were crossed with IGF-1 deficient Ames dwarf mice. Subsequently, a reduction in gliosis and amyloid-β (Aβ) plaque deposition were observed in this mouse model. This supported the hypothesis that IGF-1 may contribute to the progression of the disease.
To assess the role of IGF-1 in AD, 9-10-month-old male littermate control wild type and AβPP/PS1 mice were randomly divided into two treatment groups: control and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. Mice were sacrificed after 7 days of daily injection and the brains, spleens, and livers were collected to quantify histologic and biochemical changes. The PPP-treated AβPP/PS1 mice demonstrated attenuated insoluble amyloid-β. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment in the hippocampus. Our data suggest IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway, even at mid-life, was enough to attenuate aspects of the disease phenotype. This suggests that small molecule therapy targeting the IGF-1R pathway may be viable for late-stage disease treatment.
The Gut Microbiome Changes Shortly Before Death in Centenarians
Extremely old people have such high mortality rates that studies such as this one here become practical, answering the question of how the gut microbiome changes in the final decline into death. It is well established that the gut microbiome is influential on health, and undergoes detrimental changes across the course of adult life, although it remains to be determined as to which of the possible mechanisms are most important. In particular, it is unclear as to whether gut microbiome changes provoke inflammatory immune dysfunction or whether age-related immune dysfunction allows more inflammatory microbes to prosper. Or whether both directions of causation are relevant.
Several studies have revealed certain unique characteristics of gut microbiome in centenarians. We established a prospective cohort of fecal microbiota and conducted the first metagenomics-based study among centenarians. The objective was to explore the dynamic changes of gut microbiota in healthy centenarians and centenarians approaching end of life and to unravel the characteristics of aging-associated microbiome. Seventy-five healthy centenarians participated in follow-up surveys and collection of fecal samples at intervals of 3 months. Data pertaining to dietary status, health status scores, cause of disease and death, and fecal specimens were collected for 15 months.
Twenty participants died within 20 months during the follow-up period. The median survival time was 8-9 months and the mortality rate was 14.7% per year. The health status scores before death were significantly lower than those at 3 months before the end of the follow-up period. At this time, the participants mainly exhibited symptoms of anorexia and reduced dietary intake and physical activity. Metagenomics sequencing and analysis were carried out to characterize the gut microbiota changes in the centenarians during their transition from healthy status to death.
Analysis showed a significant change in gut microbiota from 7 months prior to death. All participants were grouped with 7 months before death as cut-off; no significant difference in α diversity was found between the two groups. Analysis revealed significant changes in the abundance of ten bacterial species before death; of these, eight species were significantly reduced (Akkermansia muciniphila, Alistipes finegoldii, Alistipes shahii, Bacteroides faecis, Bacteroides intestinalis, Butyrivibrio crossotus, Bacteroides stercoris, and Prevotella stercorea) while two were significantly increased before death (Bifidobacterium longum and Ruminococcus bromii). We speculate that these changes might occur before the clinical symptoms of deterioration in health status.
Overexpression of VRK-1 Extends Life Span in Nematode Worms
A great many approaches exist to slow aging in short-lived laboratory species such as nematodes, flies, and mice. The example here is an illustrative example, similar to dozens of other discoveries regarding life span and upregulation or downregulation of the expression of specific proteins. Since cellular biochemistry is a connected web of interactions, most such methods involve adjusting different parts of the same underlying system of regulation. An increased operation of cellular stress responses is the most common such regulator of the pace of aging. Unfortunately this type of intervention has much larger effects on life span in short-lived species than it does in long-lived species. This has led to much of the field of aging research focusing on projects that appear interesting in mice, but cannot possibly produce large gains in human life span.
Mitochondria are essential subcellular organelles for cellular energy production. Mitochondria also play important functions in a wide array of other cellular processes, ranging from cellular signaling to apoptosis. In addition, mitochondria play crucial roles in organismal aging, and functional declines in mitochondria are associated with age-related diseases. However, mild inhibition of mitochondrial respiration has been shown to promote longevity in multiple species. In Caenorhabditis elegans, the genetic inhibition of mitochondrial respiration genes prolongs life span. Inhibition of mitochondrial respiration also increases life span in Drosophila and mammals.
Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), a critical cellular energy sensor that increases life span in multiple species, is one of the factors required for the enhanced longevity caused by inhibition of mitochondrial respiration in C. elegans. The vaccinia virus-related kinase (VRK) family consists of three serine-threonine protein kinases (VRK1 to VRK3) in mammals, which are related to casein kinases. Among these three, the best characterized is VRK1, a cell cycle regulator that is abundant in proliferative tissues. Unlike mammals, C. elegans has a single VRK ortholog, VRK-1, whose function in cell proliferation is relatively well established. However, it remains unknown whether VRK-1 acts in postmitotic cells or has a role in adult life span.
In this study, we sought to elucidate the role of VRK-1 in regulation of adult life span in C. elegans. We found that overexpression of VRK-1::GFP (green fluorescent protein), which was detected in the nuclei of cells in multiple somatic tissues, including the intestine, increased life span. Conversely, genetic inhibition of vrk-1 decreased life span. We further showed that vrk-1 was essential for the increased life span of mitochondrial respiratory mutants. We demonstrated that VRK-1 was responsible for increasing the level of active and phosphorylated form of AMPK, thus promoting longevity.
A Fisetin Variant, CMS121, Slows Disease Progress in an Alzheimer’s Mouse Model
The research materials here are of interest because fisetin has been shown to be a senolytic compound in mice, capable of selectively destroying harmful senescent cells. Other senolytics have reversed the progression of Alzheimer’s disease pathology in mouse models of the condition. Destroying senescent cells in the brain reduces inflammatory signaling, and chronic inflammation is a significant mechanism in neurodegenerative conditions such as Alzheimer’s disease. Whether this compound works well as a senolytic in humans has yet to be established – a clinical trial is underway, so hopefully we’ll find out in the next year or two.
The researchers here are not interested in cellular senescence at all, however, and instead base their work on the effects of fisetin and fisetin-like molecules on lipid metabolism in the brain. Back in 2014, they showed that fisetin slowed the onset of Alzheimer’s like symptoms in mice. The present work is much the same, except with an improved version of fisetin called CMS121. This all raises the question of whether their approach is working for the reasons that they think it is working.
Over the last few decades, researchers have studied how a chemical called fisetin, found in fruits and vegetables, can improve memory and even prevent Alzheimer’s-like disease in mice. More recently, the team synthesized different variants of fisetin and found that one, called CMS121, was especially effective at improving the animals’ memory, and slowing the degeneration of brain cells.
In the new study, researchers tested the effect of CMS121 on mice that develop the equivalent of Alzheimer’s disease. The team gave a subset of the mice daily doses of CMS121 beginning at 9 months old – the equivalent of middle age in people, and after the mice have already begun to show learning and memory problems. The timing of the lab’s treatment is akin to how a patient who visits the doctor for cognitive problems might be treated, the researchers say. After three months on CMS121, at 12 months old, the mice were given a battery of memory and behavior tests. In both types of tests, mice with Alzheimer’s-like disease that had received the drug performed equally well as healthy control animals, while untreated mice with the disease performed more poorly.
To better understand the impact of CMS121, the team compared the levels of different molecules within the brains of the three groups of mice. They discovered that when it came to levels of lipids – fatty molecules that play key roles in cells throughout the body – mice with the disease had several differences compared to both healthy mice and those treated with CMS121. In particular, the researchers pinpointed differences in something known as lipid peroxidation – the degradation of lipids that produces free radical molecules that can go on to cause cell damage. Mice with Alzheimer’s-like disease had higher levels of lipid peroxidation than either healthy mice or those treated with CMS121.
Considering the Use of Lasers to Break Down Harmful Protein Aggregates
It is possible to tailor the frequency of laser light to selectively disrupt the bonds or structure of particular arrangements of molecules – such as, say, the harmful protein aggregates found in neurodegenerative and other age-related conditions. Researchers here showcase early work into the disruption of amyloids, a class of altered of proteins that feature prominently in numerous conditions. The challenge in this sort of approach is usually not that of achieving the desired disruption, but rather doing so without the delivery of so much energy, released as heat, that the process kills surrounding cells and tissues. Past early stage efforts have floundered on that problem.
A notable characteristic of several neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, is the formation of harmful plaques that contain aggregates – also known as fibrils – of amyloid proteins. Unfortunately, even after decades of research, getting rid of these plaques has remained a herculean challenge. Thus, the treatment options available to patients with these disorders are limited and not very effective.
In recent years, instead of going down the chemical route using drugs, some scientists have turned to alternative approaches, such as ultrasound, to destroy amyloid fibrils and halt the progression of Alzheimer’s disease. Now, a research team has used novel methods to show how infrared-laser irradiation can destroy amyloid fibrils. While laser experiments coupled with various microscopy methods can provide information about the morphology and structural evolution of amyloid fibrils after laser irradiation, these experiments have limited spatial and temporal resolutions, thus preventing a full understanding of the underlying molecular mechanisms. On the other hand, though this information can be obtained from molecular simulations, the laser intensity and irradiation time used in simulations are very different from those used in actual experiments. It is therefore important to determine whether the process of laser-induced fibril dissociation obtained through experiments and simulations is similar.”
The scientists used a portion of a yeast protein that is known to form amyloid fibrils on its own. In their laser experiments, they tuned the frequency of an infrared laser beam to that of the “amide I band” of the fibril, creating resonance. Scanning electron microscopy images confirmed that the amyloid fibrils disassembled upon laser irradiation at the resonance frequency, and a combination of spectroscopy techniques revealed details about the final structure after fibril dissociation. For the simulations, the researchers employed a technique that a few members of the current team had previously developed, called “nonequilibrium molecular dynamics (NEMD) simulations.” Its results corroborated those of the experiment and additionally clarified the entire amyloid dissociation process down to very specific details. Through the simulations, the scientists observed that the process begins at the core of the fibril where the resonance breaks intermolecular hydrogen bonds and thus separates the proteins in the aggregate. The disruption to this structure then spreads outward to the extremities of the fibril.
Should Rapamycin be Prescribed Ubiquitously as an Anti-Aging Supplement?
Should rapamycin be prescribed ubiquitously as an anti-aging supplement? That is the question the authors of this commentary ask after a short overview of what is known of the beneficial effects of rapamycin on mechanisms relevant to aging. Research into inhibition of the two mTOR complexes, mTORC1 and mTORC2, via compounds such as rapamycin, is well funded at the present time. Numerous companies are attempting to push mTOR inhibitors through clinical trials. It is perhaps the largest outgrowth of research into the slowing of aging produced by the practice of calorie restriction, in which benefits are largely mediated by an increased efficiency of the cellular housekeeping processes of autophagy. The question at the end of the day is whether the effect sizes here are large enough to chase hard, in comparison to those that can be obtained via exercise or calorie restriction, given that we know that exercise and calorie restriction have only a limited effect on the shape of human aging. We should aim higher.
mTOR (mammalian target of rapamycin) plays a significant role in age-related stem cell dysfunction through various mechanisms highlighting its potential as an anti-aging target to rejuvenate stem cell function. In fact, mTOR regulates many of the hallmarks of aging. A breakthrough study in 2009 showing the lifespan extending properties of rapamycin in genetically heterogenous mice led to significant research into rapamycin as an anti-aging intervention. Since that time, rapamycin has been well studied in aging and age-related functional decline mainly through the modulation of autophagy, mitochondrial function, insulin signaling, and senescence.
TOR is a heavily conserved serine/threonine kinase with homologues in several eukaryotes from yeast to humans, highlighting its importance in cellular processes. The mammalian version, mTOR exists as two distinct complexes, mTOR1 and mTOR2 that are structurally and functionally different. The mTOR1 complex acts as a central nutrient sensor and regulator of cell proliferation, growth, and survival. mTOR2 activity is usually preserved during acute rapamycin treatment but prolonged exposure can reduce mTOR2 activity as well. Hyperactive mTOR activity with aging seems to have deleterious consequences in somatic stem cells, especially muscle-derived stem cells.
Rapamycin and other compounds have been demonstrated to have significant senotherapeutic effects (i.e. selective ability to restore or eliminate senescent cells). Not only has rapamycin has been demonstrated to reduce senescence in muscle-derived stem cells by our group, but others have demonstrated that blocking mTOR reduces stem cell senescence and associated secretory phenotypes.
Should rapamycin be prescribed ubiquitously as an anti-aging supplement? There is certainly a preponderance of evidence demonstrating the safety of rapamycin in healthy and aged humans that has been well reviewed. Since its approval in 1999 by the FDA, rapamycin has been used by millions of patients with very few mild but reversible side effects. However, one possible strategy is likely intermittent treatment at higher doses for prolonged periods of time. We additionally propose that a combinatorial approach may be in order to target senescence at multiple nodes (inhibition of anti-apoptotic pathways and mTOR) directly through the use of multiple senotherapeutic agents such as fisetin and rapamycin. Overall, the plethora of preclinical and clinical data using rapamycin strongly suggests that targeting mTOR and/or senescence is a promising therapeutic strategy to mitigate aging-related phenotypes and restore stem cell health and function.
Exercise May Aid in Resisting Frailty and Cognitive Decline in Part via Effects on the Gut Microbiome
The gut microbiome is influential on long-term health, and its quality declines with age. Microbial populations that produce beneficial metabolites such as butyrate or propionate decline in number, replaced by microbial populations that invade tissue and cause chronic inflammation. Physical exercise influences health and the gut microbiome, but as noted here, the evidence for exercise to beneficially regulate these microbial populations largely results from animal studies. Data in humans is still comparatively lacking, even though epidemiological studies strongly suggest a relationship between exercise and a better gut microbiome.
Although the general characteristics of the gut microbiome in healthy people are not yet completely defined, the gut microbiomes of people with disease (e.g. metabolic syndrome, physical frailty, cognitive dysfunction, etc.) show a gradual change toward an imbalanced composition compared to those in healthy people. These imbalanced microbiome characteristics may contribute to disease onset and may play a role in a vicious cycle.
Age-related changes in the composition and diversity of the gut microbiome aggravate the immune system to regulate inflammatory responses. Collapse of the immune system causes age-related diseases. The gut microbiome is related to the immune system in that both vary in composition with age. Although the gut microbiota of humans is determined to some extent at birth, the composition continually changes throughout life according to the external environment. This age-dependent gut microbiome is closely correlated with host inflammation and pathophysiology as the host ages. The gut physiology induced by this altered gut microbiome can cause host sensitivity to microbiota, leading to chronic and severe inflammatory responses.
Exercise can significantly alter the composition of the gut microbiome, although the mechanism by which this occurs remains unclear. Some studies have assessed the effects of exercise as a treatment on metabolic disorders in mice with diabetes. When db/db (type 2 diabetes) and db/+ (control) mice were made to exercise at a low intensity, the proportion of Bifidobacterium spp. increased in the db/+ mice that exercised. In another study, wild-type mice were subjected to voluntary wheel running for 12 weeks. After the exercise intervention, the Bacteroidetes:Firmicutes ratio increased, preventing diet-induced obesity. In addition, 4-week-old C57BL/6J mice that were made to exercise on a treadmill had an increased relative abundance of Butyricimonas and Akkermansia.
It is difficult to elucidate the long-term effects of exercise in humans because the gut microbiota is influenced by several genetic and environmental factors. For this reason, previous studies have primarily sought to demonstrate the correlation between the gut microbiome and physical function. These studies have shown that the gut microbiome has distinct characteristics. This led to the hypothesis that improvements in physical function through exercise training could also be associated with the gut microbiome. Therefore, it is important to study alterations in the gut microbiome according to the type and intensity of exercise. However, to our knowledge, no studies have determined which exercise types (e.g., resistance or aerobic exercise) are more effective in influencing the gut microbiome.
Mitochondrial Dysfunction in Monocytes of the Innate Immune System Contributes to Inflammaging
Inflammaging is the name given to the constant activation of the immune system that occurs in older individuals. Inflammation is useful and necessary in the short term, for the destruction of pathogens and damaged cells, or to recruit immune cells to aid in regeneration and clearance of metabolic waste. When inflammation continues without resolution, however, it becomes very harmful to tissue function. The chronic inflammation of aging has many contributing causes: the accumulation of senescent cells and their pro-inflammatory signaling; changes in the gut microbiome that favor inflammatory microbial species; persistent infections by viral pathogens such as cytomegalovirus; and so forth. Here, researchers look at how monocytes of the innate immune system change with age, becoming more inflammatory in response to the aging tissue environment.
Monocytes are circulating cells of the innate immune system which participate in a breadth of host defense and inflammatory processes, including antigen presentation, phagocytosis, inflammatory cytokine and chemokine production, and extravasation into tissue followed by differentiation to macrophages or dendritic cells. As a principal circulating inflammatory cell, monocytes have long been speculated to be major contributors to the age-associated chronic inflammatory state often termed “inflammaging”. Because inflammaging is thought to underlie the bulk of age-related chronic diseases, monocytes are potential therapeutic targets for strategies meant to ameliorate aging-related disease.
Within the context of aging, multiple previous studies have found profound monocyte and macrophage dysfunction, including increased basal inflammation, impaired inflammatory activation, altered phagocytosis, and impaired migration/chemotaxis. In recent years, a variety of cellular metabolic programs have been shown to be linked to immune cell functions. However, immunometabolic studies have not been extensively undertaken in the aging field, and whether aging triggers shifts in immune cell metabolic programs is not well-understood.
We were the first to demonstrate that aging impaired mitochondrial function in monocytes when we showed that isolated human classical monocytes displayed reduced mitochondrial respiratory capacity. Now researchers have demonstrated a gene transcription pattern in isolated CD14+ classical monocytes from older individuals suggestive of a decrease in mitochondrial function and oxidative phosphorylation and, concomitantly, an increase in glycolytic energy production. Subsequent experiments found increased reactive oxygen species (ROS) production and enhanced glucose uptake in unstimulated monocytes from older adults.
In addition to increased ROS and decreased mitochondrial spare capacity, the researchers noted trends toward increased mitochondrial mass and reduced mitochondrial membrane potential in monocytes from older adults, and using these assays in tandem demonstrated that mitochondrial membrane potential was substantially decreased on a per mitochondrion basis. Overall, classical monocytes from older adults appeared to have a degree of mitochondrial dysfunction which may increase reliance on glycolytic metabolism during a quiescent state, and this may cause the increase in basal inflammatory activity in monocytes demonstrated here and in previous studies.
Astaxanthin as a Geroprotective Compound
Astaxanthin, a pigment compound produced by some types of algae and yeast, has been investigated for its effects on the expression and activity of proteins known to be related to the pace of aging, such as FOXO3 and klotho. At least one company is working on drug candidates derived from astaxanthin. Given the behavior of other candidate geroprotective compounds with these targets, we shouldn’t be holding our collective breath waiting on sizable benefits to lifespan. The effect size on aging as a whole tends to be modest at best, even given clinically useful benefits for specific medical conditions. The open access paper here provides a summary of recent work on this topic.
In recent years, the scientific interest in natural compounds with geroprotective activities has grown exponentially. Among the various naturally derived molecules, astaxanthin (ASX) represents a highly promising candidate geroprotector. By virtue of the central polyene chain, ASX acts as a scavenger of free radicals in the internal membrane layer and simultaneously controls oxidation on the membrane surface. Moreover, several studies have highlighted ASX’s ability to modulate numerous biological mechanisms at the cellular level, including the modulation of transcription factors and genes directly linked to longevity-related pathways.
One of the main relevant evolutionarily-conserved transcription factors modulated by astaxanthin is the forkhead box O3 gene (FOXO3), which has been recognized as a critical controller of cell fate and function. Moreover, FOXO3 is one of only two genes shown to robustly affect human longevity. Due to its tropism in the brain, ASX has recently been studied as a putative neuroprotective molecule capable of delaying or preventing brain aging in different experimental models of brain damage or neurodegenerative diseases. Astaxanthin has been observed to slow down brain aging by increasing brain-derived neurotrophic factor (BDNF) levels in the brain, attenuating oxidative damage to lipids, protein, and DNA and protecting mitochondrial functions. Emerging data now suggest that ASX can modulate Nrf2, FOXO3, Sirt1, and Klotho proteins that are linked to longevity. Together, these mechanisms provide support for a role of ASX as a potential geroneuroprotector.