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- Towards a Better Understanding of Particulate Air Pollution and Dementia Risk
- The Negligible Senescence of Sea Urchins
- Reviewing Proteomic Studies of Cellular Senescence
- The Genomic Rearchitecture of Cellular Senescence
- Reuse of a Small Molecule to Increase Autophagy in the Brain is Trialed for Alzheimer’s Disease
- Longer Female Life Spans Vary Widely by Species and Likely Have Complex Roots
- BCL-xL as a Longevity Gene
- Antibodies that Target Toxic Amyloid-β Oligomers
- Exercise Training Increases Capillary Density in a Mouse Model of Heart Failure
- Targeting the Failure of Mitophagy as a Basis for Treating Age-Related Disease
- The Role of Autophagy in the Beneficial Effects of Exercise
- Exercise Increases Ubiquitination to Clear Damaged Proteins
- Promoting Autophagy to Restore Function in the Aging Liver
- Stem Cell Therapy Reverses Aspects of Photoaging in Skin
- Engineering Viruses that Only Replicate in Cancer Cells
Towards a Better Understanding of Particulate Air Pollution and Dementia Risk
There is evidence for particulate air pollution to raise the risk of age-related diseases via mechanisms such as increased levels of chronic inflammation. While the burden of age-related disease varies widely from region to region, establishing the relative weight of specific contributions is a challenge. Poverty, particulate air pollution, high rates of chronic infection, and other environmental factors thought likely to lead to a greater risk of age-related disease all tend to overlap to some degree.
Thus while there are plausible mechanisms for particulate air pollution to spur chronic inflammation and thus speed the onset of age-related disease, and these mechanisms are well-demonstrated in laboratory animals, one cannot rule out the possibility that it is nonetheless the case that much of the observed differences in life expectancy and incidence of age-related conditions in human populations are primarily a result of worse access to medical resources. Or differences in culture that lead to differing levels of physical activity or differences in diet that add up over time. And so forth.
That said, some of the more recent epidemiological research on this topic uses comparison populations that allow for the elimination of most of the uncertainties. The results strongly suggest that exposure to wood smoke or exposure to coal smoke accelerates cardiovascular disease and reduces life expectancy. It isn’t just cardiovascular disease: all of the more common age-related conditions with a strong inflammatory component are candidates for this sort of effect. That includes forms of dementia, as the two articles here discuss.
Air Pollution and Dementia – Through Hazy Data, Links Emerge
Overall, scientists are reporting that people with the highest exposures to pollutants are more likely to get dementia. Some of the risk may lie in chronic deterioration of the cardiovascular and cerebrovascular systems. Alas, researchers are finding that particulate matter can also get into the brain through olfactory nerves or across the blood-brain barrier, whereupon they may affect neurons and glia directly. Diffuse Aβ plaques, hyperphosphorylated tau, and aggregates of α-synuclein have been detected in olfactory bulbs in the brains of young people who lived in Mexico City, where air pollution is high.
With the field heating up, are epidemiologists ready to claim that air pollution increases a person’s risk for dementia? “I think we are comfortably suspicious. The toxicology suggests it is biologically plausible, but there’s a lot of diversity in the exposure and outcome data. Air pollution is similar to other risk factors. There is a signal that may be far from certain but is strong enough to warrant more attention.” Some researchers call air pollution a gerogen. “It accelerates aging, weakens blood vessels in the brain, and promotes amyloid production. The argument that air pollution is a risk factor for dementia is doubly strong because it also accelerates atherosclerosis, which is a risk factor independently of everything else.”
The Air We Breathe – How Might Pollution Hurt the Brain?
For decades, studies of pulmonary and vascular systems dominated the air-pollution-research landscape. Researchers paid scant attention to the brain, which they considered safely ensconced behind the blood-brain barrier. But the science has begun to change. Evidence has been steadily trickling in that exposure to ambient air pollution, even at levels near the upper limits set by the World Health Organization, can affect the central nervous system. ver the last decade, numerous epidemiological studies have tied pollution to increased risk for cognitive decline and dementia.
Though the data is often equivocal, scientist are asking just how do pollutants damage the brain? Chronic deterioration of the cardiovascular and cerebrovascular systems may be to blame, but researchers are also finding that particulate matter gets into the central nervous system, either through olfactory nerves or across the blood-brain barrier, and then harms neurons and glia directly. Olfactory nerves in the nose carry a variety of cargo into the brain. In the case of pollutants, the research has focused on ultrafine particles (UFPs). At less than 0.1 micrometers in diameter, UFPs are even smaller than PM2.5. The EPA does not regulate them, hence they are not routinely monitored in the U.S. Researchers are setting up their own monitoring equipment to measure levels in ambient air that is pumped into animal facilities. While this research is still coming in, it already indicates these small particles could be particularly harmful. “This has become a topic of great interest, but we need much more data on the olfactory system.”
The Negligible Senescence of Sea Urchins
Aging as we understand it is almost a universal phenomenon in animals. Clearly there is something advantageous in evolutionary terms in having disposable individuals carry the immortal germline forward in time. One possibility is that aging is an emergent property of the fact that selection pressure is always going to fall more heavily on younger individuals, and thus evolution favors change in the direction of biological systems that are highly effective in youth but fall apart later on. Resources directed towards long-term maintenance subtract from resources directed towards immediate reproductive success. It is a brutal zero-sum race to the bottom, driven by the mortality of predation and a hostile environment. Younger individuals contribute more to the fitness of a species, because fewer of them have been eaten or otherwise removed from the picture.
Another view is that immortal species do have certain advantages in certain situations, and will emerge over time in any period of stability. They will vanish in eras of environmental change or hardship, however, outcompeted by species that age, as aging makes them more likely to adapt successfully. This viewpoint predicts the present situation, in which there exist only a very few species that appear not to age (as for hydra), or to age negligibly to various degrees (lobsters, sea urchins, naked mole-rats, and so forth). But at root, these evolutionary theories are all based on models and hypotheses, and thus prone to shift in and out of favor over time. Proof is hard to come by in this field.
Some varieties of sea urchin are among the small number of species that show very few signs of aging. Like many of their negligibly senescent peers they are capable of proficient regeneration, and the details of their aging (or lack of said) is in fact quite poorly studied in comparison to what is known of mammalian biochemistry in unusually long-lived species such as naked mole-rats. Even simpler data can be poorly characterized: maximum life span is an entirely speculative number for many sea urchin species, for example. It is only known that the number is quite large.
Senescence and Longevity of Sea Urchins
Echinoids, known as sea urchins, are a relatively small class of marine invertebrates with just over 1000 extant species. Historically, sea urchins served as model organisms in developmental biology. Later on, their properties were expanded to studying the innate immune system. Recently, the sea urchin was suggested as a novel model for studying longevity and senescence. Sea urchins are organisms of great lifespan diversity; some of which show extreme longevity. A noteworthy example is the red sea urchin, Mesocentrotus franciscanus, which has been confirmed to live well over 100 years with some specimens reaching 200 years. Conversely, the green sea urchin, Lytechinus variegatus, has an estimated maximal life expectancy of only four years. The lifespan diversity between different sea urchin species and the extreme longevity that some species achieve raises questions about their aging process. Do sea urchins age? Are there any indications of aging?
Aging in many organisms is accompanied by the complex mechanism of senescence, which involves a substantial number of biological processes which have different characteristics, such as genomic instability, telomere shortening, mitochondrial dysfunction, loss of proteostasis, stem cell exhaustion, and changes in intracellular communications. In some multicellular organisms, these processes can be so slow to the point where they might be considered negligible. Organisms that fit the criteria for negligible senescence display no noticeable increase in age-specific mortality or decrease in reproduction rate with age, as well as no noticeable weakening in their physiological capacity or disease resistance. Sea urchins grow indeterminately and reproduce throughout their entire adult life.
The lack of age-associated telomere shortening has been observed in both long-lived and short-lived sea urchins. Analysis from several adult M. franciscanus samples indicated continuous telomerase expression and maintenance of telomeres. Lifelong telomerase activity was also reported in another species of sea urchin, Echinometra lucunter. Even though telomere shortening has been suggested to be a tumor-protective mechanism and despite neoplasia occurring in diverse species of marine invertebrates, neoplasms are rarely seen in sea urchins.
Sea urchins do not fit within the classic understanding of biological aging. Members of this class are among the oldest animals on earth and it is apparent that the hallmarks of aging do not apply in their case. Considering the lack of senescence and sequencing revealing a genetic relation to humans, it is clear why researchers suggest the sea urchin is a novel model for studying aging. However, the research on sea urchins from that point of view is relatively new. At the end of the last century, even the centenarian sea urchin M. franciscanusm was thought to live just above 30 years. It was only in 2003 that carbon-14 dating exposed evidence of nuclear weapon testing from the 1950s in tissues of M. franciscanus and thus confirmed its exceptional lifespan. Further, work from 2012 was, to the best of our knowledge, the first and only global approach study on age-related gene expression in sea urchins. Since the evidence of negligible senescence is similar across short- and long-lived sea urchins, the mechanism of their mortality remains poorly understood. Therefore, further research is required.
Reviewing Proteomic Studies of Cellular Senescence
In today’s open access paper, the authors survey the work of the past decade in the use of proteomics to assess the consequences of cellular senescence. Senescent cells accumulate with age, but even in late age they remain a tiny fraction of all cells. The harms caused by the long-term presence of senescent cells occur because these cells secrete a potent mix of inflammatory signals, growth factors, and other molecules that rouse the immune system, promote fibrosis and other dysfunctions in tissue maintenance, encourage other cells to also become senescent, and so forth. This senescence-associated secretory phenotype is actually beneficial in the short term: it assists in wound healing and suppression of cancer, for example. As for so many other areas of biochemistry, too much of a good thing is not a good thing at all.
Work progresses on the commercial development of senolytic therapies capable of selectively destroying senescent cells in old tissues. In animal models of numerous age-related conditions, this class of intervention produces consistent and impressive benefits. It is literally a form of rejuvenation, removing cells that are actively maintaining a degraded, damaging state of an aged metabolism. Many age-related conditions have a strong inflammatory component, and those tested are reversed to a meaningful degree by removal of senescent cells and their pro-inflammatory signaling. Interestingly, this field is presently somewhat ahead of the ability to accurately catalog the presence and effects of senescent cells, but many research groups are working on a better understanding of senescent cells and the senescence-associated secretory phenotype. Give it a few years and the scope of available assays will catch up with the ability to remove senescent cells for therapeutic benefit.
The power of proteomics to monitor senescence-associated secretory phenotypes and beyond: toward clinical applications
The development of clinical proteomic biomarkers is an emerging and fast-growing field in human biomedical research. Recently, the focus has been developing senescence-based biomarkers of aging, frailty, and age-related diseases. Over the last decade, proteomic studies of human plasma and other biofluids have made significant progress in accurately quantifying proteins and potential biomarkers at increased depth and coverage. One of the most promising areas for these emerging technologies is therapies that target a fundamental aging process known as cellular senescence.
Cellular senescence is widely accepted as a basic driver of aging and age-related diseases. In this complex stress response, cells permanently lose the ability to proliferate and alter distal tissues through systemic and local paracrine effects. Cellular senescence can be triggered by stressors, including genotoxic agents, nutrient deprivation, hypoxia, mitochondrial dysfunction, and oncogene activation. Although senescent cells irreversibly arrest growth, they remain metabolically active and secrete many biologically active molecules, known as the senescence-associated secretory phenotype (SASP). The SASP initiates inflammation, wound healing, and growth responses in nearby cells. With age, the number of senescent cells or ‘senescence burden’ increases, and this increased senescence burden and chronic SASP drive many pathological hallmarks of aging.
Cellular senescence is an example of antagonistic pleiotropy – a trait that is beneficial early in life but detrimental later in life. In healthy tissues, the SASP is typically transient and contributes to tissue homeostasis. In contrast, the chronic presence of senescent cells and a SASP is associated with multiple age-related diseases. Eliminating senescent cells and the SASP is considered a highly promising therapeutic strategy for preventing or treating age-associated diseases and extending health span. To selectively kill senescent cells non-genetically, drugs known as ‘senolytics’ are being developed; additionally, drugs termed senomorphics or senostatics are being developed to mitigate the detrimental effects of senescent cells by modifying the SASP.
To develop clinical therapeutics that target senescent cells, it is critical to have reliable biomarkers to measure the senescent cell burden in humans both to identify patients with an elevated burden and to track the efficacy of the therapeutics. In this review, we will discuss proteomic strategies to discover senescence-derived biomarkers and their great potential for measuring the senescent cell burden. Senescent cells secrete many molecules, and the resulting SASP consists of a complex mixture of both proteins, metabolites, and other molecules. However, thorough investigation is required to determine which SASP protein factors or protein panels qualify as biomarkers to quantitatively assess the senescent cell burden, and subsequently which SASP factors can be used efficiently and accurately as a biomarker for aging and age-related diseases.
The Genomic Rearchitecture of Cellular Senescence
Cellular senescence is important in aging. Cells can become senescent in response to damage, a toxic environment, or reaching the Hayflick limit on replication. Senescent cells undergo profound changes to architecture and protein expression that halt replication, cause a growth in size, and produce a potent mix of growth factors and inflammatory signals. Over the short term, this is useful. Senescent cells aid in wound healing and cancer suppression, provided that they are soon destroyed, either by programmed cell death or the immune system. With advancing age, however, senescent cells accumulate in tissues. There is too much creation, while mechanisms of clearance become slow and erratic. The secretions of senescent cells cause chronic inflammation and tissue dysfunction when present over the long term: this is a contributing cause of aging and age-related disease.
Numerous research groups and biotech companies are involved in developing a range of senolytic therapies capable of selectively destroying senescent cells. This is a still comparatively new, but very important branch of medicine. Clearance of senescent cells is literally a rejuvenation therapy, as these errant cells are in effect actively maintaining a degraded state of tissue function. Remove them, and a portion of aging is removed. Numerous age-related conditions have been meaningfully reversed in animal studies of senolytic therapies, including surprising structural reversals such as ventricular hypertrophy.
The promise of this new field of medicine ensures that a great deal of effort is now devoted to mapping the fundamental biochemistry of senescent cells. Scientists are in search of ways to sabotage the survival mechanisms of senescent cells, or their damaging secretions. In that vein, today’s open access paper is a review of what is known of the extensive genomic reorganization exhibited by senescent cells. It is almost certainly the case that somewhere in there are novel mechanisms of selective cell destruction that will be discovered and developed for clinical use in the years ahead.
The Histone Code of Senescence
Aging is a physiological condition characterized by the functional deficit of tissues and organs due to the accumulation of senescent cells. The key role of senescence in aging is well-established. Clearance of senescent cells in mouse models delays the appearance of age-related tissue and organ diysfunctions. Senescent cells are characterized by the permanent cell-cycle arrest sustained by the accumulation of cyclin-dependent kinase inhibitors (CDKi), like p16, p21, and p27, as well as by the release of cytokines, chemokines, and soluble factors. This modified microenvironment is known as senescence-associated secretory phenotype (SASP). The senescence state is triggered by different stimuli/stressors. These include the shortening of the telomeres (replicative senescence), the oncogene-induced replication stress, the oncogene-induced senescence (OIS), the accumulation of misfolded protein and/or oxidative stress (stress-induced premature senescence, SIPS).
The impairment of the non-homologous end joining (NHEJ) and homologous recombination (HR) repair mechanisms are common traits of senescent cells. Moreover, a widespread epigenetic resetting is a character of senescent cells and sustains cell-cycle arrest and cellular survival, through the activation of (i) CDKi, (ii) tumor suppressors, and (iii) secretion of chemokines and cytokines, as well as the remodeling of the microenvironment.
Macroscopically, senescent cells are characterized by the formation of peculiar areas of heterochromatin, named as SAHF (senescence-associated heterochromatin foci), mainly at E2F loci. However, SAHF do not characterize all senescent cells and are not causally linked to the onset of senescence. Other epigenetic features, like the distension of satellites (senescence-associated distension of satellites, SADS), the re-activation of transposable elements, and of endogenous retroviruses (ERV), seem to better qualify different types of senescence. Finally, aging appears to be marked by substantial re-arrangements of the nucleosomes, with the loss of histones H3 and H4. During senescence the epigenome undergoes temporal and sequential modifications that are mandatory to accomplish different cellular adaptations. Initially, this epigenetic resetting is mainly due to the accumulation of irreparable DNA damage. After this first wave of epigenetic modifications, the epigenome is remodeled and fixed in order to sustain the permanent cell-cycle arrest and to modulate the microenvironment.
The accumulation of double strand breaks (DSBs) in DNA is a general hallmark of senescence and aging. The main endogenous sources of DSBs are telomere attrition and replicative stress. Replication stress is commonly observed in RS, OIS and aging. In all these conditions cells slow down DNA synthesis and replication fork progression. However, the reduced replication fork speed activates dormant origin to preserve replication timing during replication stress. This adaptive response allows the maintenance of an unaltered replication timing also in cells entering senescence. On the other side it exposes common fragile sites (CFSs), which are genomic loci more prone to breakage after DNA polymerase inhibition, and the accumulation of genomic alterations. CFS alterations are typically observed in pre-neoplastic lesions. Similarly, cells exposed to genotoxic agents (e.g., chemotherapeutic agents, pollutants, and toxins) or to oxidative stress activate the DDR that frequently leads to cell-cycle arrest. Whatever the origin, the accumulation of irreparable DNA damage gives rise to a response characterized by the activation of tumor suppressors and CDKi and by the release of pro-inflammatory cytokines.
Global histone loss, as well as the focused deposition of histone variants (H2AX, H2AZ, H2AJ, H3.3 and macroH2A) and the redistribution of H3K4me3, H3K27me3, and H3K36me3 characterize both DNA damage response, DSBs, and senescence. The chromatin remodeling observed in different senescence models seems to represent a temporal and spatial evolution of what is observed after a short-time treatment of the cells with DNA damaging agents. Cancer cells appear as forgetful cells that have lost the epigenetic memory of a healthy genome. Aging seems to be predisposed to this memory loss. One of the major challenges of the future, regarding the treatment of aging and cancer, will be the identification of the framework of epigenetic changes that can restore this memory.
Reuse of a Small Molecule to Increase Autophagy in the Brain is Trialed for Alzheimer’s Disease
Today I’ll point out an example of drug reuse and autophagy upregulation. The processes of autophagy are responsible for recycling molecular waste and broken cellular structures. Autophagy is upregulated in response to stress placed upon cells, whether by heat, cold, lack of nutrients, a toxic local environment, and so forth. This is beneficial to tissue function, health, and longevity, and thus there is considerable interest in the research community in producing therapies that boost the operation of autophagy. This hasn’t made a great deal of progress towards the clinic, but nonetheless in any of the sizable databases of small molecule compounds there are some that result in increased autophagy – the question is always whether the side-effects are tolerable.
The cancer research community in particular tests a great many compounds and attempts to influence a great many core cellular processes, autophagy included. So when we see attempts at drug reuse, it is often the case that the drug in question is a small molecule that is either present used, used in the past, or was at least considered for chemotherapy. In the trial noted here, the drug is nilotinib. Researchers propose that it produces the observed reduction of toxic protein aggregates in the Alzheimer’s disease brain by spurring increased autophagy, and can do so at low enough doses to avoid the worst of the side-effects noted to date. Of course, as is sadly standard in the mainstream of Alzheimer’s development, no benefit to patients was observed to accompany improvements in biomarkers. The commentary provided by the trial administrators regarding the need more patients to see possible improvements is what is normally said by trial administrators about treatments that are expected to have only small and unreliable beneficial effects.
This is all par for the course. An entirely too sizable fraction of modern medical development centers not around the development of new therapies, based on new advances in science, but rather finding existing therapies that can be reused in new ways. This, I think, is one of the important underlying reasons as why most new treatments tend to be only marginally effective. The present regulatory structure makes it so costly and difficult to explore new approaches that funding entities are steered into the path of using whatever is already to hand, provided it can be shown to do at least a little good. The edifice of medical development is built of perverse incentives such as this, unfortunately.
Nilotinib Appears Safe and Affects Biomarkers in Alzheimer’s Disease Clinical Trial
Nilotinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic myeloid leukemia. Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in neurons in the brain – hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to get rid of the Tau, Abeta and other toxic proteins.
After careful screening, 37 people with mild dementia due to Alzheimer’s were randomized to either the placebo or nilotinib groups for the 12-month study. A 150 mg daily dose of nilotinib or matching placebo was taken orally once daily for 26 weeks followed by a 300 mg daily dose of nilotinib or placebo for another 26 weeks. To prevent bias the study was blinded, meaning neither the study participants nor the investigators knew if the active drug or placebo were being administered until the end of the study. Nilotinib carries an FDA “black-box warning” because of cardiovascular issues that may lead to sudden death in cancer patients (typically treated with 600 mg daily), but no such incidents occurred in this study (maximum dose of 300 mg daily).
The amyloid burden as measured by brain imaging was reduced in the nilotinib group compared to the placebo group. Two forms of amyloid in cerebrospinal fluid were also measured. Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to placebo. Hippocampal volume loss (on MRI scans of the brain) was attenuated at 12 months and phospho-tau-181 in spinal fluid was reduced at 6 and 12 months in the nilotinib-treated group.
Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer’s Disease
This phase 2 trial was underpowered (as designed) to detect differences in clinical and cognitive outcomes and focused on evidence of nilotinib effects on safety and biomarkers, hence the incongruity between biomarker and clinical effects. Nevertheless, exploratory outcomes included efficacy of nilotinib versus placebo on the change from baseline to 6 months and 12 months. As expected, no differences were observed between the placebo and nilotinib groups on clinical, cognitive, functional, and behavioral outcomes, suggesting that a larger multicenter phase 3 study must be adequately powered to examine potential efficacy. The exploratory clinical outcomes in this phase 2 study will guide the design of an adequately powered larger and longer study to evaluate the safety and efficacy of nilotinib in Alzheimer’s disease.
Longer Female Life Spans Vary Widely by Species and Likely Have Complex Roots
In most species, including our own, females live longer than males. Why this is the case is likely one of those simple questions that lacks a simple answer. At the root of it all are evolutionary pressures relating to sex-specific differences in mating strategy, but that says little about how and why an emergent property such as sex-specific life span differences actually emerges. Researchers here find a great deal of variation from species to species in the degree of the female longevity advantage, complicating the picture.
The researchers compiled demographic data for more than 130 wild mammal populations and were able to estimate the average longevity and the rate of increase in the risk of dying as a function of age for both sexes. The analyzes led to unexpected results. Not only do females generally live longer than males in wild mammals, but the difference in longevity between the sexes, although very variable depending on the population, in the vast majority of cases exceeds the difference observed in human populations. The average female wild mammal lives 18.6% longer than her male counterpart. In humans the difference is “only” 7.8%. The greatest differences are found in animals like Common brushtail possum, lion, killer whale, moose, greater kudu, and sheep.
For about half of the mammal populations studied, the increased risk of mortality with age is actually more pronounced in females than in males. These results show that the larger longevity of females than males is most likely due to other factors that affect individuals during their entire adult life. To reach this conclusion, researchers calculated the average age at death, as well as the rate at which mortality increases with age.
There is a common belief that males engage in potentially dangerous sexual competitions and live riskier lives than females, and that this could account for their shorter lifespan. Contrary to this idea, this study reveals that the intensity of sexual selection does not directly modulate the amplitude of the differences in longevity observed between the sexes. The results rather suggest that complex interactions between the physiological characteristics specific to each sex and local environmental conditions are at play.
Why do the females live longer? One explanation is that males often are larger and put more energy in sexual characters such as growing larger horns than females. This requires energy, and if the animals live in a harsh climate, the males may be more vulnerable to these extreme environmental conditions. Another explanation is that males produce more androgens than females. Androgens modulate immune performance and when present at high levels, they can impair some aspects of the immune defense, making males more susceptible to infections and diseases.
BCL-xL as a Longevity Gene
BCL-xL is a mitochondrial protein that acts to suppress the programmed cell death response of apoptosis, and is overexpressed in some cancers, as well as in senescent cells. Thus small molecules that bind to BCL-xL have been used as chemotherapeutics and more recently as senolytics that selectively destroy senescent cells. That removal of senescent cells is a legitimate rejuvenation therapy that quite literally turns back aging in animal models has caused greater attention to be given to BCL-2 family proteins and their role in allowing cells to hold back apoptosis.
Separately, as noted here, evidence shows that BCL-xL is a longevity-associated protein, which is interesting, to say the least. This may or may not have anything to do with suppression of apoptosis – or if it does, one has to argue that keeping apoptosis-inclined cells alive for longer is on balance beneficial, despite being detrimental in the matter of senescent cells, or that apoptosis is complex and situational. This may be the case, but it is always challenging to tease out the specific contributions to any observed outcome of this nature. Another possibility is that greater levels of BCL-xL improve mitochondrial function in some way, but more work is needed to establish whether or not this is a plausible mechanism.
We have studied centenarians, as an example of successful aging, and have found that they overexpress BCL-xL. By performing functional transcriptomic analysis of peripheral blood mononuclear cells (PMBC), we compared the expression patterns of 28,869 human genes in centenarians, septuagenarians, and young people. Results showed that the mRNA expression pattern of centenarians was similar to the one of young people, and completely different from that of septuagenarians. In particular, sub-network analysis of the 1,721 mRNAs that were found to be statistically different between the three populations, converged on the following six genes: interferon-γ (IFNG), T-cell receptor (TCR), tumor necrosis factor (TNF), SP1 transcription factor, transforming growth factor-β1 (TGFβ1), and cytokine IL-32.
Likewise, those six genes were related to BCL-xL, Fas, and Fas ligand (FasL), all of them known to be involved in the control of cell death regulation. However, where BCL-xL is an antiapoptotic protein, Fas and FasL are proapoptotic. This could be considered a paradox, as centenarians overexpress anti and proapoptotic proteins at the same time, but there is an explanation: BCL-xL is involved in the inhibition of the intrinsic pathway of apoptosis, which is mainly mediated by mitochondria and activated after self-cell stress; however, Fas and Fas-L induce the extrinsic pathway of apoptosis, which means that they force the cell to die after external stress signals. This suggests that centenarians have a better way to control apoptosis when cells are aging (intrinsic apoptosis), but at the same time, damaged cells by external signals are removed more efficiently (extrinsic apoptosis).
In order to further demonstrate the role of BCL-xL in longevity, we performed longevity curves using C. elegans with a gain function of Ced-9, the ortholog for human BCL-xL. Interestingly, animals overexpressing Ced-9 showed a significant increase in both the mean and the maximum survival time. Although aging is a multifactorial process, these studies suggest that BCL-xL function is relevant in aging and may be one of the factors that contributes to exceptional longevity.
Antibodies that Target Toxic Amyloid-β Oligomers
One possible expansion of present immunotherapies for Alzheimer’s disease is to more specifically track and target oligomeric forms of amyloid-β. Efforts to reduce amyloid-β in the brain have, after many years of failure, started to succeed in that goal in human trials, but patients are not exhibiting benefits as a result. It remains to be seen whether or not this is because amyloid-β is a trigger for other self-sustaining pathological mechanisms, such as cellular senescence of supporting cells in the brain, and thus removing it does little good once Alzheimer’s is underway. An alternative view is that perhaps the wrong forms of amyloid-β are being targeted by existing approaches, and a more specific therapy would achieve better results.
Researchers have designed an antibody which is highly accurate at detecting toxic amyloid-beta oligomers and quantifying their numbers. “There is an urgent unmet need for quantitative methods to recognise oligomers – which play a major role in Alzheimer’s disease, but are too elusive for standard antibody discovery strategies. Through our innovative design strategy, we have now discovered antibodies to recognise these toxic particles.”
Alzheimer’s disease, the most prevalent form of dementia, leads to the death of nerve cells and tissue loss throughout the brain, resulting in memory failure, personality changes and problems carrying out daily activities. Abnormal clumps of proteins called oligomers have been identified by scientists as the most likely cause of dementia. Although proteins are normally responsible for important cell processes, according to the amyloid hypothesis, when people have Alzheimer’s disease these proteins – including specifically amyloid-beta proteins – become rogue and kill healthy nerve cells.
Proteins need to be closely regulated to function properly. When this quality control process fails, the proteins misfold, starting a chain reaction that leads to the death of brain cells. Misfolded proteins form abnormal clusters called plaques which build up between brain cells, stopping them from signalling properly. Dying brain cells also contain tangles, twisted strands of proteins that destroy a vital cell transport system, meaning nutrients and other essential supplies can no longer move through the cells.
“While the amyloid hypothesis is a prevalent view, it has not been fully validated in part because amyloid-beta oligomers are so difficult to detect, so there are differing opinions on what causes Alzheimer’s disease. The discovery of an antibody to accurately target oligomers is, therefore, an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control.” The lack of methods to detect oligomers has been a major obstacle in the progress of Alzheimer’s research. This has hampered the development of effective diagnostic and therapeutic interventions and led to uncertainty about the amyloid hypothesis.
Exercise Training Increases Capillary Density in a Mouse Model of Heart Failure
Exercise is known to improve outcomes in heart failure patients, but there is a limit as to the data that can be obtained on mechanisms of action from human patients. Here researchers use a mouse model of heart failure to show that exercise doesn’t impact the harmful presence of fibrosis in heart tissue, but does increase capillary density. The density of capillaries in tissues throughout the body declines with age, and this progressive loss is probably quite important in a number of aspects of aging, particularly in tissues that have high energy demands, such as the heart. That fibrosis isn’t affected suggests that exercise doesn’t do much to reduce the burden of cellular senescence, however, given that senescent cells are strongly implicated in age-related fibrosis.
Heart failure with preserved ejection fraction (HFpEF) is the most common type of heart failure in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecular mechanisms by which exercise training induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that exercise training might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery.
Here, we show that aged (24-30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, exercise training in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion.
Interestingly, RNAseq showed that exercise training did not significantly modulate the biological pathways targeted by conventional HF medications. However, it reversed multiple age-related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how exercise training potentially reverses cardiac aging phenotypes in HFpEF.
Targeting the Failure of Mitophagy as a Basis for Treating Age-Related Disease
Evidence strongly suggests that the global faltering of mitochondrial function throughout the body with advancing age has a lot to do with a decline in the effectiveness of mitophagy. Mitochondria are the power plants of the cell, a herd of hundreds swarming and replicating like bacteria in every cell to produce the chemical energy store molecule ATP. Mitophagy is the specialized form of autophagy that destroys worn and damaged mitochondria, recycling their component parts. Without it, cells would become overtaken by broken, malfunctioning mitochondria. Mitochondrial dysfunction leads to too little ATP, but also higher levels of harmful oxidative molecules that stress cells. In energy-hungry tissues such as muscle, the heart, the brain, loss of mitochondrial function is thought important in the progression of age-related conditions.
Mitophagy serves as a critical mechanism to eliminate damaged mitochondria and is regulated by multiple mechanistically distinct pathways. Cellular level studies have provided valuable insight into the signaling pathways regulating mitophagy, as well as mapping out how and when mitophagy occurs in a wide range of physiological and pathological conditions to counter cellular stressors such as reactive oxygen species or damaged mitochondria. A better understanding of mitochondrial turnover mechanisms, with an improved focus on how these pathways might contribute to disease pathogenesis, should allow for the development of more efficient strategies to battle numerous pathological conditions associated with mitochondrial dysfunction.
Mitophagy is an important element of overall mitochondrial quality control. Defective mitophagy is thought to contribute to normal aging as well as various neurodegenerative and cardiovascular diseases. In fact, aging by itself is a major risk factor for the pathophysiology of cardiovascular and neurodegenerative diseases. Increasing evidence suggests that mitophagy failure accelerates aging. Interestingly, a marked age-dependent decline in mitophagy has been observed in the hippocampus of the mouse brain, an area where new memory and learning are encoded. This strengthens the hypothesis that mitophagy might regulate neuronal homeostasis and that a decline in mitophagy might predispose to age-dependent neurodegeneration. Age-related mitochondrial function deterioration is underlined as a key feature of other diseases, such as obesity, diabetes, and cancer. Therefore, maintaining a healthy mitochondrial network via functional mitophagy may serve as an attractive therapeutic strategy in the treatment of a wide range of age-related diseases, and potentially regulate longevity.
The emergence of nutritional and pharmacological interventions to modulate autophagy/mitophagy and to serve as a potential therapeutic model is quite encouraging. Accumulation of ubiquitinated outer mitochondrial membrane proteins has been proposed to act as a signal for selective mitophagy. Ubiquitination of mitochondrial proteins is positively regulated, in part, by the E3 ubiquitin ligase, Parkin. In contrast, removal of ubiquitin is achieved by the action of resident mitochondrial deubiquitinases, most notably USP30, thereby acting to antagonize mitophagy. Inhibition of USP30 enzyme activity may provide an unambiguous avenue to pursue the role of mitophagy as a therapeutic target.
Recently, three promising candidates that may stimulate and reinvigorate mitophagy process have been demonstrated to reduce the accumulation of amyloid-beta and phosphorylated tau in Alzheimer’s mouse brains. These compounds, including nicotinamide mononucleotide, urolithin A, and actinonin, can improve symptoms of AD and dementia symptoms in preclinical models. In addition, Tat-Beclin 1 peptide, derived from a region of the autophagy protein, beclin 1, can promote autophagy/mitophagy and improve mitochondrial function in heart failure animal models. Therefore, identifying more efficient and specific agents that can modulate the clearance of defective mitochondria are likely to have significant therapeutic benefits.
The Role of Autophagy in the Beneficial Effects of Exercise
Autophagy is the name given to a collection of processes responsible for recycling damaged or otherwise unwanted structures and proteins in the cell. With age, autophagy becomes less efficient. Many individual mechanisms falter, and the end result is that cells become more cluttered with damaged parts and harmful proteins. Scaled up across entire organs, this has a meaningful contribution to the progression of aging and age-related disease. Interestingly, increased or more efficient autophagy appears to be a centrally important mechanism in the benefits to health and longevity provided by calorie restriction and a range of other interventions that mildly stress cells. Accordingly, there is a great deal of interest in the research community in developing therapies based on upregulation of autophagy, though progress towards the clinical has been quite slow so far.
Regular exercise training helps to improve the body’s metabolism. The protective effect of exercise on the cardiovascular system has been increasingly recognized in recent years. Exercise can improve the level of cardiac autophagy, promote cardiomyocytes proliferation, reduce local tissue inflammation, and improve cardiac function. Cardiac autophagy plays a crucial role in exercise-induced cardioprotection as a stress response and is a necessary process for adaptation to exercise. However, there are still many questions to be answered in the study of the protective effects and mechanisms of autophagy as they relate to exercise training.
Exercise training for regulating autophagy can be bidirectional. Autophagy impairment and altered autophagy levels have been implicated in the pathogenesis of many diseases. Insufficient autophagy has been reported to contribute to multiple organ dysfunction and other adverse outcomes in autophagy-deficient mice as well as in ill patients, with an observed autophagy deficiency phenotype, evidenced by impaired autophagosome formation, accumulation of damaged proteins and mitochondria, and so on. Excessive autophagy characterized by lysosomal defects and an accumulation of autophagic vacuoles can play an important role in X-linked myopathy. Specifically, for cardiovascular diseases caused by insufficient autophagy, exercise training up-regulates autophagy. For cardiovascular disease caused by excessive autophagy, exercise training can inhibit autophagy, restore regular autophagy function, and delay the progression of cardiovascular disease.
Autophagy is critical in the maintenance of mitochondrial quality and oxidative stress during cardiovascular stress, while exercise can restore protein quality and increase the clearance of reactive aldehydes. Moreover, an increased basal level of cardiac autophagy improves myocardium resistance to subsequent ischemic injury. Aerobic exercise can inhibit the phosphorylation of mTOR by up-regulating the activity of AMPK, thereby improving cardiomyocytes autophagy and preventing cardiac aging and systolic and diastolic dysfunction. A single bout of exercise can also activate autophagy in the heart by activating the transcription factors FOXO3 and hypoxia-inducible factor 1 and then indirectly up-regulating Beclin 1 expression.
Exercise Increases Ubiquitination to Clear Damaged Proteins
The ubiquitin-proteasome system is one of the ways in which cells remove damaged and unwanted proteins. Proteins are tagged with ubiquitin, which allows them to enter a proteasome and be broken down into component parts for reuse. Increased proteasomal activity has been shown to be beneficial in short-lived laboratory species, with the understanding that this is because cells will maintain a lower level of damaged components, leading to improved function and lesser degrees of downstream damage. As researchers note here, cells upregulate activity of the ubiquitin-proteasome system in response to mild stress, such as that produced by exercise. This is one of the ways in which exercise produces benefits to health and function.
Physical activity benefits health in many ways, including the building and maintenance of healthy muscles, which are important for our ability to move about normally, as well as to fulfill the vital role of regulating metabolism. Maintaining muscular function is essential. Part of our ability to do so depends upon proteins – the building blocks of muscles – being degraded when worn-out and eliminated in a kind of clean up process that allows them to be replaced by freshly synthesized proteins. Now, researchers have demonstrated that a single, intense, roughly 10-minute bicycle ride results in a significant increase in the activity of ubiquitin and a subsequent intensification of the targeting and removal of worn-out proteins in muscles. This paves the way for an eventual build-up of new proteins.
“Ubiquitin itself is a small protein. It attaches itself to the amino acid lysine on worn-out proteins, after which the protein is transported to a proteasome, which is a structure that gobbles up proteins and spits them out as amino acids. These amino acids can then be reused in the synthesis of new proteins. As such, ubiquitin contributes to a very sustainable circulation of the body’s proteins. The important role of Ubiquitin for ‘cleaning-up’ worn-out proteins in connection with muscular activity was not fully appreciated. Now we know that physical activity increases ubiquitin tagging on worn-out proteins. Basically, it explains part of the reason why physical activity is healthy. The beauty is that muscle use, in and of itself, is what initiates the processes that keep muscles ‘up to date’, healthy, and functional.”
Promoting Autophagy to Restore Function in the Aging Liver
The processes of autophagy recycle damaged and unwanted structures and proteins in cells. Increased autophagy is involved in the beneficial response to calorie restriction and numerous other mild forms of stress. A range of potential approaches to upregulate autophagy have been explored by the research community, but few have made much progress towards the clinic. It is entirely possible that increased autophagy is more beneficial in some tissues than in others – or to put it another way, perhaps some tissues are much more impaired than others by age-related loss of autophagy. Some of the most impressive data has centered on improved autophagy in the aging liver via LAMP2A upregulation, showing sizable increases in function. Again, these demonstrations have yet to make the transition to clinical medicine.
Aging leads to the accumulation of lipofuscin in the lysosome, which impairs the efficiency of autophagic enzymes. Moreover, aging causes a significant decrease in the number of autophagosomes, which may be related to the decline of activation capacity of AMPK. It further reduces autophagy activity. Liver resection not only triggers liver regeneration, but also induces autophagy of hepatocytes. Autophagy plays a crucial role in liver regeneration. Liver regeneration requires abundant energy, which is among others generated by recycling intracellular macromolecules derived from damaged organelles.
Autophagy activity in aged liver is significantly reduced compared to young liver. Therefore, improving autophagy through pharmacological intervention seems to be an effective treatment to promote regeneration in senescent livers. The mTOR pathway is the most common autophagy-related pathway. However, the mTOR pathway is not only the key regulatory pathway for autophagy, but also the pathway that modulates cell proliferation. Inhibition of mTOR activity can induce autophagy, but inhibits cell proliferation at the same time. In the case of liver resection, inhibition of cell proliferation is detrimental, since it causes impairment of liver regeneration.
Therefore, modulation of autophagy via the mTOR-independent pathway is a better strategy. Strikingly different drugs such as Carbamazepine, Amiodarone, Ezetimibe, and Lithium induce autophagy via these pathways. They are of documented or putative benefit for enhancing liver regeneration and should be explored in more depth. This is of special importance for the elderly population, where liver regeneration is already impaired, in part due to the age-dependent decrease of autophagic activity.
At present, many aging patients with malignant liver disease cannot be treated effectively because of the aging-related impairment of liver regeneration. Aging-related changes also lead to decreased autophagy activity, which is an important cause for insufficient liver regeneration. Age-specific strategies to promote liver regeneration for these patients at risk are needed. Evidence is accumulating that the modulation of autophagy via pharmacological intervention is an effective approach to promote liver regeneration. This is of utmost benefit for aging patients with impaired autophagy. However, choosing the appropriate autophagy pathway to activate autophagy is crucial.
Stem Cell Therapy Reverses Aspects of Photoaging in Skin
With few exceptions, the worldwide community of clinics offering first generation stem cell therapies is not usually a source of reliable data. They don’t tend to conduct trials or even much report on the results of their work. Further, the stem cell therapies used can vary enormously in effectiveness. Cells are fickle things and tiny differences in how two groups run exactly the same protocol for sourcing and preparing cells can cause widely divergent outcomes, both between clinics, and from patient to patient for the same clinic. Not that groups are in fact usually running the same protocol; a very broad range of possibilities exist under the umbrella term “stem cell therapy.” Results in one clinic may not generalize well to other clinics; standardization has been slow to arrive. This is all worth bearing in mind when reading reports such as this one.
For a while now, some plastic surgeons have been using stem cells to treat aging, sun-damaged skin. But while they’ve been getting good results, it’s been unclear exactly how these treatments – using adult stem cells harvested from the patient’s own body – work to rejuvenate “photoaged” facial skin. A new microscopic-level study provides the answer: within a few weeks, stem cell treatment eliminates the sun-damaged elastin network and replacing them with normal, undamaged tissues and structures – even in the deeper layers of skin.
The researchers assessed the cellular- and molecular-level effects of mesenchymal stem cells (MSCs) treatment on sun-damaged (photoaged) facial skin. All 20 patients in the study, average age 56 years, were scheduled for facelift surgery. For each patient, a small sample of fat cells from the abdomen was processed to create patient-specific MSCs. The cultured stem cells were injected under the skin of the face, in front of the ear. When the patients underwent facelift surgery three to four months later, skin samples from the stem cell-treated area were compared to untreated areas.
Histologic and structural under the microscope analysis demonstrated that MSC treatment led to improvement in overall skin structure. Treated areas showed “partial or extensive reversal” of sun-related damage to the skin’s stretchy elastin network – the main skin structure affected by photoaging. In the layer immediately beneath the skin surface, the stem cell-treated areas showed regeneration of a new, fully organized network of fiber bundles and dermal extracellular matrix remodeling changes. In the deeper skin layer, “tangled, degraded, and dysfunctional” deposits of sun-damaged elastin were replaced by a normal elastin fiber network. These changes were accompanied by molecular markers of processes involved in absorbing the abnormal elastin and development of new elastin.
Engineering Viruses that Only Replicate in Cancer Cells
One of the many interesting approaches to targeting cancer cells for destruction is the use of viruses that are largely innocuous to humans, but replicate preferentially in cells exhibiting the characteristics of cancer, such as continual cellular replication. Researchers here demonstrate a way to engineer a virus to require the biochemistry of cell replication for it to also replicate, ensuring that it will affect only cancerous tissue.
Much research in recent years has investigated genetically modifying adenoviruses to kill cancers, with some currently being tested in clinical trials. When injected, these adenoviruses replicate inside cancer cells and kill them. Scientists are trying to design more efficient viruses, which are better able to target cancer cells while leaving normal cells alone. Researchers have now made two new adenoviruses that specifically target cancer cells. To do this, they used adenylate-uridylate-rich elements (AREs), which are signals in RNA molecules known to enhance the rapid decay of messenger RNAs (mRNAs) in human cells. AREs make sure that mRNAs don’t continue to code for proteins unnecessarily in cells. Genes required for cell growth and proliferation tend to have AREs.
Under certain stress conditions, however, ARE-containing mRNAs can become temporarily stabilized allowing the maintenance of some necessary cell processes. ARE-mRNAs are also stabilized in cancer cells, supporting their continuous proliferation. Researchers inserted AREs from two human genes into an adenovirus replicating gene, making the new adenoviruses: AdARET and AdAREF. AdARET and AdAREF were both found to replicate inside and kill cancer cells in the laboratory, while they hardly affected normal cells. Tests confirmed that the specific replication in cancer cells was due to stabilization of the viral genes with AREs, which did not happen in the healthy cells. The scientists then injected human cancer cells under the skin of nude mice, which then developed into tumors. When AdARET and AdAREF were injected into the tumors, they resulted in a significant reduction in tumor size.