Fight Aging! Newsletter, June 8th 2020

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."

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."

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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."

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.

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.

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.