As of the year 2021, aging is considered both an intriguing process that research attempts to understand and a universal burden that the scientific community and the industry seek to intervene with. Currently, various theories have been put forward as to how we age, which physical alterations occur during aging and how we could substantially increase healthy life span or even maximal life span. In 2013, a comprehensive review proposed a detailed framework incorporating nine hallmarks of aging to characterize this complex process. These hallmarks comprise epigenetic alterations, telomere attrition, genomic instability, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, deregulated nutrient sensing, and altered intercellular communication. Intriguingly, these attributes are highly interconnected. Here, we will focus on age-related epigenetic alterations and how targeting the epigenetic landscape might enable extension of life span.

Underlying epigenetic mechanisms such as histone modifications and DNA methylation were discovered at the end of the 20th century and now have a well-established role in the regulation of gene expression. In general, histones are bound to DNA in order to compact it to accommodate the size of the nucleus. This DNA-histone interaction is dynamic. The modifications of the tail domain of histones by small molecules can alter the interaction between the DNA and histone thus changing the accessibility of that specific genomic area.

Here, we present recent findings on epigenetic changes involving histone modifications and DNA methylation during aging and age-associated maladies such as neurodegeneration and cancer. In this regard, we also outline the emergence of DNA methylation clocks to determine biological aging. We will cover the utility of epigenetic signatures as biomarkers and the physiological implications of respective alterations. Age-associated metabolic dysregulation, which could underlie epigenetic changes, and other risk factors for age acceleration, will be described before we finally explore therapeutic interventions aiming to prevent age-associated maladies and to increase healthy life span including the emerging field of cellular reprogramming.

Parkinson's disease may be driven in part by cell stress-related biochemical events that disrupt a key cellular cleanup system, leading to the spread of harmful protein aggregates in the brain, according to a new study. Parkinson's entails the deaths of neurons in a characteristic sequence through key brain regions. The killing of one small set of dopamine-producing neurons in the midbrain leads to the classic Parkinsonian tremor and other movement impairments. Harm to other brain regions results in various other disease signs including dementia in late stages of Parkinson's.

Affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. In the new study, researchers demonstrated that a type of nitrogen-molecule reaction called S-nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates. The p62 protein normally assists in autophagy, a waste-management system that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of Parkinson's, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates.

Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown.

Here, we used cell-based models, including human induced pluripotent stem cell (hiPSC)-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathological pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular build-up of misfolded proteins, with consequent secretion resulting in cell-to-cell spread.

Thus, our data show that pathological protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for α-syn release and spread of disease throughout the nervous system.

It is almost impossible to catalogue all of the therapeutic investigations conducted and ongoing using mesenchymal stem cells (MSCs). However, the excitement in this burgeoning field has been somewhat dampened by some less than stellar clinical trial results and persistent variability of effect due to production practicalities and correlative, rather than causative, potency assays.

During these studies an immense amount of data has been generated regarding stem cell biology and possible mechanism of action in diseases, including the physiological niche where various stem cells are sourced, cell-cell contact-dependent mechanisms and a rich secretome containing small molecules, proteins, organelles and even full membrane bound bodies. Indeed, much of this data has been accumulated regardless of whether the overall subsequent clinical trials themselves were successful. These have prompted a multitude of strategies that could putatively be included in the cell manufacturing process to improve outcomes in patients.

In this review we will look at current and future strategies that might overcome limitations in efficacy. Many of these take their inspiration from stem cell niche and the mechanism of MSC action in response to the injury microenvironment, or from previous gene therapy work which can now benefit from the added longevity and targeting ability of a live cell vector. We will also explore the nascent field of extracellular vesicle therapy and how we are already seeing enhancement protocols for this exciting new drug. These enhanced MSCs will lead the way in more difficult to treat diseases and restore potency where donors or manufacturing practicalities lead to diminished MSC effect.

It is natural to try to associate the process of aging with metabolism, since all living organisms obtain the energy required to stay alive from such a process. In 1908 researchers compared the energy metabolisms and lifespans of five domestic animals (guinea pig, cat, dog, cow and horse) and humans and found that the lifespan (total) energy expenditure per gram for the five species is approximately constant, suggesting that the total metabolic energy consumption per lifespan is fixed, which later became known as the 'rate of living' theory.

Decades later, a mechanism was found by which the idea behind a fixed energy consumption per lifespan might operate, the 'free-radical damage' hypothesis of aging, in which the macromolecular components of the cell are under perpetual attack from toxic byproducts of metabolism, such as free radicals and oxidants. However, the 'free-radical' theory has lost support in recent years, with evidence that a reduction in free radicals by antioxidant supplementation in the diets of laboratory animals does not significantly increase their life expectancy.

The rate of living relation was partially confirmed for approximately one hundred mammals and was extended to birds, ectotherms, and even unicellular organisms such as protozoa and bacteria, totaling almost three hundred different species in a range of 20 orders of magnitude in body mass. Although the total metabolic energy exhausted per lifespan per body mass of a given species appears to be a relatively constant parameter - approximately a million Joules per gram of body weight for mammals - variations of more than an order of magnitude have been found among different animal classes; this result is considered the most persuasive evidence against the 'rate of living' theory.

Here, we present a universal relation that relates lifespan energy consumption to several physiological variables, such as body mass, temperature, and the ratio of heart rate to respiratory rate, which have been shown to be valid for ∼300 species representing different classes of living organisms, from unicellular organisms to the largest mammals. This relation has an average scattered pattern restricted to factors of 2, with 95% of the organisms having departures of less than a factor of π from the relation, despite the difference of ∼20 orders of magnitude in body mass.

This result can be interpreted as supporting evidence for the existence of an approximately constant total number (10^8) of respiration cycles per lifetime for all organisms studied, effectively predetermining the extension of life through the basic energetics of respiration. This is an incentive to conduct future studies on the relation of such a constant number of cycles per lifetime due to the production rates of free radicals and oxidants, or alternative mechanisms, which may yield definite constraints on the origin of aging.

Aging is a complex process indicated by low energy levels, declined physiological activity, stress induced loss of homeostasis leading to the risk of diseases and mortality. Recent developments in medical sciences and an increased availability of nutritional requirements has significantly increased the average human lifespan worldwide. Several environmental and physiological factors contribute to the aging process. However, about 40% human life expectancy is inherited among generations, many lifespan associated genes, genetic mechanisms and pathways have been demonstrated during last decades.

In the present review, we have evaluated many human genes and their non-human orthologs established for their role in the regulation of lifespan. The study has included more than fifty genes reported in the literature for their contributions to the longevity of life. Intact genomic DNA is essential for the life activities at the level of cell, tissue, and organ. Nucleic acids are vulnerable to oxidative stress, chemotherapies, and exposure to radiations. Efficient DNA repair mechanisms are essential for the maintenance of genomic integrity, damaged DNA is not replicated and transferred to next generations rather the presence of deleterious DNA initiates signaling cascades leading to the cell cycle arrest or apoptosis. DNA modifications, DNA methylation, histone methylation, histone acetylation, and DNA damage can eventually lead towards apoptosis.

Currently, research on the contribution of genes to the aging process, cellular stability, and longevity of lifespan is at initial stages. The data available is scattered, and the individual reports provide information about the contribution of selected either a gene or a group of similar genes and genetic mechanisms in the regulation of aging and lifespan. Further studies for the identification of potential genetic targets to protect against aging-associated diseases are also required. Finally, the translation of these genetic findings into clinical practice poses a big challenge.

The latest exploration into longevity research is 'controlled reprogramming', specifically of our epigenome. The term 'epigenome' is derived from 'epi', the Greek for 'above', and describes chemical changes to our DNA and DNA-associated proteins. These changes are responsible for altering gene expression patterns, but do not affect the underlying DNA sequence. This explains why cells in our body can have distinct properties and functions, despite containing identical genes. Epigenetic changes can also explain ageing (or so it is hoped), hence reversing epigenetic changes may be the key to reversing ageing altogether.

The basis of controlled reprogramming relies on Yamanaka factors - four transcription factors that can be used to remodel the epigenome of a differentiated cell, such as a skin cell, and return it to an undifferentiated state. Ten years after Shinya Yamanaka received the Nobel prize for his discovery of these eponymous factors, a Silicon Valley startup, Altos Labs, has placed a three billion bet on the ability of three of these factors to reverse ageing.

Will their bet pay off? Author and scientist Andrew Steele remain unconvinced. Whilst Steele does not doubt that we will see anti-ageing treatments in the near future, he is hesitant to name Altos Labs as their source. He described the ten hallmarks of the ageing process, of which epigenetic changes are only one. Other hallmarks include the accumulation of senescent cells and the shortening of telomeres, caps on the end of our chromosomes that are degraded each time a cell divides. The net result of all these hallmarks, including epigenetic modifications, is the manifestation of ageing in the form of cancer, heart disease, wrinkles, memory loss, diabetes, and general decline. The premise that three simple transcription factors, the Yamanaka factors, could prevent all this suffering might just be too good to be true.

There are examples of age-related changes that can't necessarily be reversed by controlled reprogramming. One example is collagen, an extremely long-lived protein that is replaced very slowly, if at all. Collagen and similar proteins form an extracellular matrix that is vital for maintaining the integrity of nearby cells. Rejuvenating these cells without repairing the extracellular matrix would leave cells unsupported, proving a futile effort. "If reprogramming works, it might be that other treatments are needed in combination with it to realise its true potential, and it would be a great shame if we've failed to develop them in the meantime."

Inhibition of the master growth regulator mTORC1 slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling.

ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

Mesenchymal stem cells (MSCs) are recognized as potential treatments for multiple degenerative and inflammatory disorders as a number of animal and human studies have indicated their therapeutic effects. There are also several clinically approved medicinal products that are manufactured using these cells. For such large-scale manufacturing requirements, the in vitro expansion of harvested MSCs is essential. Multiple subculturing of MSCs, however, provokes cellular senescence processes which is known to deteriorate the therapeutic efficacy of the cells. Strategies to rejuvenate or selectively remove senescent MSCs are therefore highly desirable for fostering future clinical applications of these cells.

In this present study, we investigated gene expression changes related to cellular senescence of MSCs derived from umbilical cord blood and found that CD26, also known as DPP4, is significantly upregulated upon cellular aging. We further observed that the inhibition of CD26 by genetic or pharmacologic means delayed the cellular aging of MSCs with their multiple passaging in culture. Moreover, the sorting and exclusion of CD26-positive MSCs from heterogenous cell population enhanced in vitro cell attachment and reduced senescence-associated cytokine secretion. CD26-negative MSCs also showed superior therapeutic efficacy in a mouse model of lung emphysema. Our present results collectively suggest CD26 is a potential novel target for the rejuvenation of senescent MSCs for their use in manufacturing MSC-based applications.

A blood test has proven highly accurate in detecting early signs of Alzheimer's disease in a study involving nearly 500 patients from across three continents, providing further evidence that the test should be considered for routine screening and diagnosis. The blood test assesses whether amyloid plaques have begun accumulating in the brain based on the ratio of the levels of the amyloid beta proteins Aβ42 and Aβ40 in the blood.

Researchers have long pursued a low-cost, easily accessible blood test for Alzheimer's as an alternative to the expensive brain scans and invasive spinal taps now used to assess the presence and progression of the disease within the brain. Evaluating the disease using PET brain scans - still the gold standard - requires an average cost of 5,000 to 8,000 per scan. Another common test, which analyzes levels of amyloid-beta and tau protein in cerebrospinal fluid, costs about 1,000 but requires a spinal tap process that some patients may be unwilling to endure.

This study estimates that prescreening with a 500 blood test could reduce by half both the cost and the time it takes to enroll patients in clinical trials that use PET scans. Screening with blood tests alone could be completed in less than six months and cut costs by tenfold or more, the study finds. Known as Precivity AD, the commercial version of the test is marketed by C2N Diagnostics. The current study shows that the blood test remains highly accurate, even when performed in different labs following different protocols, and in different cohorts across three continents.

The cystine/glutamate antiporter system xc- has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT-/-) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT-/- mice led to the hypothesis that system xc- deletion would negatively affect life- and healthspan. Still, till now the role of system xc- in physiological aging remains unexplored.

We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT-/- mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT+/+ mice, was attenuated in xCT-/- mice.

While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT-/- mice. Targeting system xc- is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.

Skeletal muscle stem cells, or satellite cells (SCs), are indispensable for repairing damaged muscle and are key targets for treating muscle diseases. In healthy uninjured muscle, these reserve stem cells lie in quiescence, a dormant state, to maintain the resident stem cell pool for future muscle repair. When muscle damage occurs, these quiescent muscle stem cells will quickly "wake up", generating enough muscle progenitor cells to build new muscle. Despite being a critical step in muscle regeneration, the muscle stem cell quiescence-to-activation transition remains an elusive process.

Recently, using a whole mouse perfusion technique to obtain the true quiescent SCs for low-input mass spectrometry analysis, a team of scientists revealed that a regulating protein called CPEB1 is instrumental in reprogramming the translational landscape in SCs, hence driving the cells into activation and proliferation. "Our analysis shows that levels of CPEB1 protein are low in quiescent SCs, but upregulated in activated SCs, with loss of CPEB1 delaying SC activation."

In their subsequent RNA immunoprecipitation sequencing analysis and CPEB1-knockdown proteomic analysis, the researchers found that CPEB1 phosphorylation regulates the expression of the crucial myogenic factor MyoD - a protein involving in skeletal muscle development - by targeting some of the sequences found within the three prime untranslated region (3'UTR) of the target RNA transcript to drive SC activation. "It means that the manipulation of CPEB1 levels or phosphorylation can increase SC proliferation to generate enough myogenic progenitor cells for muscle repair, which could be a potential therapeutic target for muscle repair in the elderly."

In most mammals, neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ) continues during adulthood. In rodents and non-human primates, new neurons generated in the SVZ migrate to the olfactory bulb. In humans, on the other hand, the addition of new neurons to the olfactory bulb is likely negligible and new neurons produced in the SVZ migrate to the neighboring striatum. Growing evidence suggests that the decline in neurogenesis observed during aging in mammals is due to increased quiescence of neural stem cells (NSCs) and progenitors (hereafter progenitors refers to both NSCs and progenitors).

Studies in rodents have shown that adult NSCs arise from a population of quiescent radial glial cells that accumulate embryonically. Rather than being a static non-proliferating pool of cells, studies in rodents have demonstrated that they are a very dynamic population of cells that transit between proliferative and quiescent states. With aging progenitors become less plastic and remain mainly quiescent, which prevents depletion of the progenitor pool. The mechanisms that regulate quiescence of progenitors are just beginning to be unraveled.

We have previously identified CD271 as a marker expressed by progenitors of the aged human SVZ. The present study assesses the molecular identity of CD271-positive progenitors from the SVZ of the aged human brain at single-cell level and investigates a mechanism through which human progenitors could be maintained in a quiescent state. We identify the secreted frizzled-related protein-1 (SFRP1), an inhibitor of the Wnt signaling pathway, to be among genes whose expression changes over time. We demonstrate that inhibition of SFRP1 with a small molecule stimulates proliferation in vitro, in human iPSC-derived NSCs, and in vivo in early postnatal mice. Altogether, our work proposes a mechanism that maintains quiescence of progenitors of the human SVZ, which opens up future possibilities to stimulate NSCs of the human brain to promote repair.

Your average 80-year-old has lost over 30 per cent of the muscle mass they had as a young adult. Without exercising to counteract the loss of muscle mass, humans already start to lose muscle around age 30. The body has two basic types of muscle fibres: the slow-twitch (type I) muscle fibres needed for endurance activities, and the fast-twitch (type II) muscle fibres used for short bursts of strength. As we age, we primarily lose type II muscle mass. "Our experiments show that CYTOR contributes to increased development of precisely the type II muscle fibres."

The next step for the researchers was to take a closer look at what happens when gene therapy is used to increase CYTOR levels. Using the CRISPR-Cas9 method, the researchers increased CYTOR production in live animals and in precursors to muscle cells from older humans. The results are very promising. "In human cells, CYTOR production increased as a result of gene therapy. We also observed that the therapy stimulated the cells to promote the development of fast-twitch type II muscle."

Experiments with mice confirmed that gene therapy not only provides a theoretical effect at the cellular level, but can actually provide improved muscle function. Gene therapy, which increased CYTOR production in the calf muscles of ageing mice, gave the mice increased muscle mass, better grip strength in their hind legs and greater running capacity. When the researchers reduced CYTOR production in young mice, however, the mice developed weaker muscles and more inflammation and cell death in the muscles. "The CYTOR gene seems to be absolutely crucial in order to maintain normal muscle function."

Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders characterized by cognitive impairment and functional decline increasing with disease progression. Within non-pharmacological interventions, transcranial direct current stimulation (tDCS) might represent a cost-effective rehabilitation strategy to implement cognitive abilities with positive implications for functional autonomy and quality-of-life of patients. Our systematic review aimed at evaluating the effects of tDCS upon cognition in people suffering from AD and PD. We searched for randomized controlled trials (RCTs). Three review authors extracted data of interest, with neuropsychological tests or experimental cognitive tasks scores as outcome measures.

A total of 17 RCTs (10 trials for AD and 7 trials for PD) were included. Compared with sham stimulation, tDCS may improve global cognition and recognition memory in patients with AD and also some executive functions (i.e., divided attention, verbal fluency, and reduction of sensitivity to interference) in patients with PD. Criticism remains about benefits for the other investigated cognitive domains. Despite preliminary emerging evidences, larger RCTs with common neuropsychological measures and long-term follow-ups establishing longevity of the observed effects are necessary for future research in applied psychology field, alongside improved clinical guidelines on the neurodegenerative disorders pertaining electrodes montage, sessions number, duration and intensity of the stimulation, and cognitive battery to be used.