Clearly, several trials have shown that targeting aging is feasible in humans. Calorie restriction has been associated with protective cardiovascular effects (lowered blood pressure and improved lipid profile), improved mitochondrial biogenesis, and metabolic efficiency (increased insulin sensitivity). A drawback of calorie restriction is that the feasibility is quite low for most humans. NAD+ supplements are safe in humans and increase NAD+-related metabolites but the influence on cellular energy-sensing pathways, and aging itself, has not shown clear results. Trials with senolytics have shown promising systemic results in subjects with idiopathic pulmonary fibrosis, diabetes, and kidney dysfunction. Nevertheless, senescence is an essential anti-cancer mechanism and interfering with this may be associated with cancer development. Further, mTOR inhibition causes improved mitochondrial function, dermatological skin improvements, and overall improved immune function in elderly individuals, possibly by lowering immunosenescence.

An important feature of potential aging drugs must be a relative absence of side-effects. Here, the benefit of utilizing wide-spread drugs that are approved for treatment of other diseases is that safety and tolerability is already thoroughly investigated, making it possible to commence larger-scale trials sooner. However, if treatment duration is prolonged periods of time, the health gaining effects must outweigh potential side-effects. For example: Dasatinib can cause gastrointestinal bleeding and liver damage. A possible approach to avoid this may be combining medication, i.e., handling rapamycin-caused glucose dysmetabolism with metformin

A bump on the road for expansion of aging trials is the inclusion of mainly healthy subjects in current anti-aging clinical trials, as long lists of wide-spread morbidities and medication often are among exclusion criteria. Thus, studies may include only exceptionally healthy elderly where effects of therapies targeting aging may be less efficient. Further, this could cause a blind-spot in catching potential side-effects of aging treatments as the side-effects may be related to other conditions. Instead, one could consider having slightly less stringent inclusion criteria which would allow individuals with mild chronic diseases (eg. hypertension) to be included. Similarly, an estimated 1/3 of all elderly receive five or more prescription drugs, potentially resulting in missed drug-drug interactions.

Medication often has a therapeutical concentration window, where too little poses no effect and too much is toxic. The same principle is relevant in anti-aging treatment but may include an additional temporal aspect. Initiation of some anti-aging treatments may require early intervention and might not be efficient if subjects are already old, while other treatment forms may show promising results in the elderly but cause unwanted, harmful side-effects in healthy, young subjects. This temporal therapeutical window has been experimentally observed in cancers and could cause major issues for anti-aging clinical trials. If no effect of a treatment is observed due to "incorrect" age of subjects or if it simply has no effect in any age-group can only be investigated by comparing identical studies on different age-groups.

In conclusion, clinical trials targeting aging in humans have shown promising but limited results on biomarkers so far.

The lengthening of the human lifespan is associated with a rise in the burden of age-associated neurological disorders. Indeed, the aging process is characterized by a progressive shift from a homeostatic balance of inflammatory markers towards a "primed" or sensitized state. This increased neuroinflammatory priming makes the aged brain further susceptible to the disruptive effects of intrinsic and extrinsic factors like disease, infection, and stress, thereby elevating the risk of affective disorders, cognitive impairments, and neurodegenerative diseases in the aged population.

In addition to aging, chronic inflammatory conditions are increasing. Elevated chronic low-grade inflammation among modern urban societies may be caused by decreased microbial exposures - this is the foundation for the "Old Friends" hypothesis. Throughout evolution, the mammalian immune system developed tolerance to commensal environmental microbes. One such example is Mycobacterium vaccae (M. vaccae), a saprophytic bacterium found in soil, water, and mud that our ancestors frequently encountered. Reintroduction of these microbes in an excessively "clean" environment can suppress immune sensitization and reduce the risk for inflammatory diseases. M. vaccae has immunoregulatory properties, such as enhancing the induction of regulatory T cells and stimulating their production of anti-inflammatory cytokines, including interleukin (IL)-10 and transforming growth factor β. Peripheral immunization with M. vaccae also promotes an anti-inflammatory milieu in the central nervous system (CNS).

Elevated neuroinflammatory priming, as is observed due to aging, is mediated in part by microglia, the primary immunocompetent cell in the CNS. Microglia are dynamic cells that take on an array of phenotypes based on signals from their surrounding microenvironment. When microglia detect adverse signals or molecules, their morphology can drastically change.

Here, we investigate whether aging-related shifts in microglial morphology are ameliorated by immunization with anti-inflammatory M. vaccae. Morphological features of microglia evaluated in the amygdala, hippocampus, hypothalamus, and prefrontal cortex of adult (3 mos) and aged (24 mos) male rats. Our results demonstrate that aging leads to differential changes in microglia morphology and reactivity across brain regions, with the hippocampus being the most sensitive. Moreover, microglia in the amygdala and hippocampus appear most responsive to the anti-inflammatory effects of M. vaccae immunization, protecting against some age-associated microglia morphological changes.

Researchers have engineered 3D human spinal cord tissues and implanted them in an animal model with long-term chronic paralysis, demonstrating high rates of success in restoring walking abilities. Now, the researchers are preparing for the next stage of the study, clinical trials in human patients. They hope that within a few years the engineered tissues will be implanted in paralyzed individuals enabling them to stand up and walk again.

"Our technology is based on taking a small biopsy of belly fat tissue from the patient. This tissue, like all tissues in our body, consists of cells together with an extracellular matrix comprising substances like collagens and sugars. After separating the cells from the extracellular matrix we used genetic engineering to reprogram the cells, reverting them to a state that resembles embryonic stem cells - namely cells capable of becoming any type of cell in the body."

The human spinal cord implants were then implanted in two different groups of animal models: those who had only recently been paralyzed (the acute model) and those who had been paralyzed for a long time (the chronic model) - equivalent to one year in human terms. Following the implantation, 100% of the animals with acute paralysis and 80% of those with chronic paralysis regained their ability to walk. Encouragingly, the model animals underwent a rapid rehabilitation process, at the end of which they could walk quite well.

Cell therapy using induced pluripotent stem cell-derived neurons is considered a promising approach to regenerate the injured spinal cord (SC). However, the scar formed at the chronic phase is not a permissive microenvironment for cell or biomaterial engraftment or for tissue assembly. Engineering of a functional human neuronal network is now reported by mimicking the embryonic development of the SC in a 3D dynamic biomaterial-based microenvironment. Throughout the in vitro cultivation stage, the system's components have a synergistic effect, providing appropriate cues for SC neurogenesis. While the initial biomaterial supported efficient cell differentiation in 3D, the cells remodeled it to provide an inductive microenvironment for the assembly of functional SC implants. The engineered tissues are characterized for morphology and function, and their therapeutic potential is investigated, revealing improved structural and functional outcomes after acute and chronic SC injuries. Such technology is envisioned to be translated to the clinic to rewire human injured SC.

Cellular deregulation of amyloid formation is implicated in many neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease (PrD), and diseases affecting other parts of the body such as cataracts, Type II Diabetes, and Corneal Dystrophy (CD). Fifty different proteins or peptides involved in such amyloid aggregation disorders are structurally and functionally characterized. Typically amyloid fibrils are generated from highly amyloidogenic peptide regions of a protein as the result of protein misfolding, genetic mutations, or undesired proteolytic cleavage of that protein.

However, not all amyloid fibril formation results in detrimental diseases while some may be important to fulfil a biological function and take place in well-modulated and highly contingent condition. In some cases, functional amyloids are controlled by a balance between peptide production and clearance of amyloids, reduction in the production of oligomeric seeds, minimizing interaction of oligomeric seeds with other aggregation-prone proteins via compartmentalization and the presence of an inherent disaggregation mechanism. Understanding why certain amyloids are toxic while others are biologically important may reveal important information on the function of these amyloids or develop novel treatment avenues in amyloid associated diseases.

In order to remove toxic amyloid build-up in the cell during cellular stress, some protozoans such as yeasts are equipped with molecular machines capable of disaggregating diverse amyloid and nonamyloid structures. In yeast, several types of heat shock proteins (HSPs) are discovered to work together to form disaggregation machinery. This machinery reduces the toxic amyloid species present in the cell and restores the native function of the protein buried in the amyloids via an amyloid disaggregation process. Metazoans such as mammals might experience less cellular stress resulting in the rapid build-up of toxic amyloid in the intracellular environment but are susceptible to accumulation of both intracellular and extracellular amyloids in various pathological conditions. To disaggregate these toxic amyloids in the extracellular environment, metazoans are equipped with ATP-independent chaperones such as HtrA1 and L-PGDS instead of the ATP-dependent HSPs, found in yeast. To deal with intracellular amyloids, the metazoan cells are also equipped with other types of HSPs i.e., Hsp110, Hsp70, Hsp40, and other smaller proteins from the heat shock protein families. These diverse disaggregation mechanisms evolved to reverse the formation of the toxic amyloids and survive through cellular stress and preclude amyloid-related pathogenicity.

In neurodegenerative diseases such as Alzheimer's disease, aggregates resulting from amyloidogenic peptides deposit into senile plaques which later leads to neurofibrillary tangles, synaptic dysfunction, and neuronal cell death. In each disease, a specific peptide or protein aggregates to form amyloid fibrils. There is no effective therapeutic solution that is capable of reversing the formation of these aggregates. Amyloid disaggregation seems to be a viable option where these amyloid fibrils can be broken down into non-toxic aggregates and this would possibly help to mitigate the toxic effects caused by these amyloid fibrils. In this review, we mainly focus of the disaggregation and the remodulation of the preformed fibrils into smaller molecular weight species by different disaggregating agents instead of the inhibition of fibril formation or aggregation. Many protein disaggregases have shown promising results in in vitro studies where pathogenic amyloids fibrils are solubilized through the action of these disaggregases. These studies will be discussed in this review to showcase the potential of using amyloid disaggregation as a treatment for several neurodegenerative diseases.

Including nearly 20,000 participants, the largest study on amyloid prevalence to date estimates that a third of cognitively normal people older than 70 have amyloid building up in their brains. Compared amyloid prevalence across age, cognitive status, ApoE genotype, and by biomarker modality (i.e., CSF versus PET). A total of 10,139 participants in 50 cohorts had undergone amyloid-PET scans, while 8,958 participants across 51 cohorts had had CSF Aβ42 measured; only 1,571 underwent both.

Among those without dementia, amyloid cropped up in 24 percent of those with normal cognition, 27 percent of people with subjective cognitive decline, and 51 percent of people with mild cognitive impairment. Findings were similar whether amyloid-PET or CSF Aβ42 was used. Amyloid prevalence increased with age among those without dementia. For example, based on the adjusted CSF Aβ42 measurements, 17 percent of cognitively normal people between the ages of 50-54 had evidence of amyloid. By age 70, a third did, and by age 95, more than half did.

The size of this study gave the researchers enough statistical power to compare amyloid prevalence across different ApoE genotypes. E4/E4 carriers started accumulating amyloid at the youngest age, followed by E3/E4, E2/E4, E3/E3, and E2/E3 carriers. Notably, the amyloid prevalence among E3/E4 carriers was 10 percent higher than it was among E2/E4 carriers across all groups without dementia, highlighting a protective effect of the E2 allele.

From lower animals to humans, every species is endowed with a certain degree of regeneration. For example, axolotl, the Mexican salamander, is evolutionarily primitive vertebrate known to possess a higher regenerative capacity than mammals. Another example is the deer antler, which is the only organ capable of complete regeneration in mammals. In most mammals, the limited anatomical and functional recovery capabilities reside in young tissue and decline with age, leading to compromised tissue repair after injury. Compared to stem cells from regenerative tissues of the axolotl limb and the deer antler, human stem cells, such as human mesenchymal stem cells (hMSCs), possess a relatively limited capacity for regenerative repair of damages to vital tissues and organs, but gradually lose such capacity with age. Whether molecular characteristics between these naturally occurring regeneration processes are evolutionarily conserved across species is unknown.

Using comparative methods to describe the similarities and differences between species is a powerful strategy to discover the regulatory mechanisms that underline vital life events, such as regeneration. Here, we sought to understand how metabolic regulation intersects with inherent regenerative capacity using comparative approaches. Samples for this study included i) species that are more primitive on the evolutionary scale but can renew entire organs, and ii) higher species in evolution that have lost full organ regenerative capacity but retain a limited capacity for tissue repair. We systematically depicted metabolic profiles in various regeneration-related contexts, and we discovered that high pyrimidine and fatty acid metabolism was shared across species, tissues, and cells with high regenerative capacity. We identified uridine as a pro-regenerative metabolite that promoted human stem cell activity and enhanced regeneration in multiple tissues in mammals. These observations will open new avenues for metabolic intervention in tissue repair and regeneration.

Our cells contain mitochondria, which provide the energy for our cells to function. Each of these mitochondria contains a tiny amount of mitochondrial DNA. Faults in our mitochondrial DNA can affect how well the mitochondria operate, leading to mitochondrial diseases, serious and often fatal conditions. There are typically around 1,000 copies of mitochondrial DNA in each cell, and the percentage of these that are damaged, or mutated, will determine whether a person will suffer from mitochondrial disease or not. Usually, more than 60% of the mitochondria in a cell need to be faulty for the disease to emerge, and the more defective mitochondria a person has, the more severe their disease will be. If the percentage of defective DNA could be reduced, the disease could potentially be treated.

Researchers recently used a biological tool known as a mitochondrial base editor to edit the mitochondrial DNA of live mice. The treatment is delivered into the bloodstream of the mouse using a modified virus, which is then taken up by its cells. The tool looks for a unique sequence of base pairs - combinations of the A, C, G and T molecules that make up DNA. It then changes the DNA base - in this case, changing a C to a T. This would, in principle, enable the tool to correct certain 'spelling mistakes' that cause the mitochondria to malfunction.

There are currently no suitable mouse models of mitochondrial DNA diseases, so the researchers used healthy mice to test the mitochondrial base editors. However, it shows that it is possible to edit mitochondrial DNA genes in a live animal. "This is the first time that anyone has been able to change DNA base pairs in mitochondria in a live animal. It shows that, in principle, we can go in and correct spelling mistakes in defective mitochondrial DNA, producing healthy mitochondria that allow the cells to function properly."

The Memory and Aging Project (MAP), has been leading a longitudinal, prospective study since 1997 with volunteers who agree to undergo periodic cognitive and psychomotor assessments and to donate their organs for scientific purposes after death. The design of this study makes it possible to correlate daily habits and health states directly with structural and functional alterations in the brains of the participants.

The latest publication of that project presents results for 404 individuals whose physical activity was monitored with wristwatch or wristband-based devices for an average of 3.5 years ante-mortem. After death, samples were collected from up to twelve brain areas essential for cognitive and psychomotor skills; quantitative and functional analyses of eight synaptic proteins were performed on these samples, and a comprehensive histopathological evaluation, which examines ten neuropathologies associated with ageing, was made.

The results confirmed that higher rates of daily physical activity are associated across the board with an enrichment in the quantity and functionality of all the synaptic proteins analysed. This association was found to be most pronounced in brain regions related to motor control, such as the caudate nucleus and putamen. Furthermore, the relationship between physical exercise and synaptic density was independent of both the neuropathological load found in the same brain areas and the presence of pathologies affecting motor skills, indicating that physical activity can be beneficial for any elderly person regardless of their health status.

However, when analysed longitudinally, data indicated that the beneficial effects of physical exercise are highly volatile, as those participants with a high physical routine during early life and who discontinued this habit in the last two years of life had synaptic densities similar to those observed in more sedentary participants. In short, this study shows that physical exercise, even at an advanced age, contributes either towards promoting synaptogenesis processes or towards increasing synaptic resilience against the deleterious effects of neuropathological lesions."

Based on meta-analyses and data from the Global Burden of Disease study, we used life table methodology to estimate how life expectancy (LE) changes with sustained changes in the intake of fruits, vegetables, whole grains, refined grains, nuts, legumes, fish, eggs, milk/dairy, red meat, processed meat, and sugar-sweetened beverages. We present estimates for an optimized diet and a feasibility approach diet. An optimal diet had substantially higher intake than a typical diet of whole grains, legumes, fish, fruits, vegetables, and included a handful of nuts, while reducing red and processed meats, sugar-sweetened beverages, and refined grains. A feasibility approach diet was a midpoint between an optimal and a typical Western diet.

A sustained change from a typical Western diet to the optimal diet from age 20 years would increase LE by more than a decade for women from the United States (10.7 years) and men (13.0 years). The largest gains would be made by eating more legumes (females: 2.2; males: 2.5), whole grains (females: 2.0; males: 2.3), and nuts (females: 1.7; males: 2.0), and less red meat (females: 1.6; males: 1.9) and processed meat (females: 1.6; males: 1.9). Changing from a typical diet to the optimized diet at age 60 years would increase LE by 8.0 years for women and 8.8 years for men, and 80-year-olds would gain 3.4 years. Change from typical to feasibility approach diet would increase LE by 6.2 years for 20-year-old women from the United States and 7.3 years for men.

In conclusion, a sustained dietary change may give substantial health gains for people of all ages both for optimized and feasible changes. Gains are predicted to be larger the earlier the dietary changes are initiated in life.

Data from the Framingham Study suggests that hypertension doubles the risk of stroke in older adults age 65-94, with a relative risk of 1.9 in men and 2.3 in women. While hypertension treatment has been shown to reduce stroke risk, it is less clear when stroke reduction occurs. In contrast, the harms of hypertension treatment, which include orthostatic hypotension, syncope, falls, and electrolyte abnormalities, appear to occur soon after treatment initiation. For example, the risk of falls and fractures was found to be increased in the first 7 to 45 days after the initiation of antihypertensive medications. Thus, while hypertension treatment decreases stroke risk over time, it can also lead to an increased risk for adverse effects.

To help clinicians identify, which patients are most likely to benefit from hypertension treatment (and which patients are more likely to be harmed), our objective was to determine the TTB of hypertension treatment for the primary prevention of stroke. We conducted a survival meta-analysis of major randomized clinical trials to determine the time to benefit (TTB) for various stroke absolute risk reduction (ARR) thresholds.

We determined that 200 adults aged ≥65 years would need to be treated for 1.7 years to avoid 1 stroke (ARR = 0.005). Since the overwhelming majority of older adults have a life expectancy of more than 1.7 years, these results suggest that almost all older adults with hypertension would benefit from treatment. We found substantial heterogeneity across studies suggesting that for older adults with poorly controlled hypertension, systolic blood pressure (SPB) higher than 190 mmHg, the TTB to prevent 1 stroke for 200 persons treated is likely substantially shorter than 1.7 years. Conversely, for older adults with relatively well-controlled hypertension (i.e., SBP less than 150 mmHg), the TTB to prevent 1 stroke for 200 persons treated is likely substantially longer than 1.7 years.

All 70- to 77-year-olds in Trondheim were invited to the Generation 100 study in 2012. Those who agreed to participate were randomly assigned to five years of exercise of various kinds. One group would primarily do high intensity intervals, a second group would mainly go for walks or do other exercise with moderate intensity, and the last group would try to follow the activity recommendations of the health authorities to be physically active for at least 150 minutes each week.

"Our results show that organized training follow-up may have given older men, but not older women, better cognitive function and lowered the probability of mild cognitive impairment. But all in all, it seems that the most important thing is that you actually train in a way that increases your fitness, regardless of whether you get organized help to be physically active or not."

In the groups that received follow-up with high-intensity training and training with moderate intensity, respectively, we found somewhat greater loss of brain volume in deep areas of the brain than among those who trained themselves. But we have to emphasize that everyone in the Generation 100 study - regardless of the form of exercise they did - had less brain loss than expected for people in their 70s. The group that trained on their own without organized follow-up had the least shrinkage in the hippocampus and thalamus.

The 70-77-year-old participants on average had the same cognitive abilities after five years as at start-up, and that during the study period they even improved on some of the tests. The results show that being in good shape like the Generation 100 participants were, is important for maintaining good brain function.

Sustained mitochondrial fitness relies on coordinated biogenesis and clearance via mitophagy. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology.

We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response (UPRmt), orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

Among sensory dysfunctions, loss in the sense of smell, olfaction, is particularly pronounced in older age. Olfactory deficits are associated with a number of health conditions such as depressive symptoms and frailty, as well as shorter survival. An important fact is that olfactory impairment has exceptionally high prevalence rates among patients with neurodegenerative diseases and may constitute one of the first noncognitive manifestations of an impending dementia.

Given that the olfactory system is directly exposed to the outside environment, it has been speculated that part of the olfactory loss observed in older age may arise from cumulative damage of xenobiotics. For example, an increased exposure to air pollution may lead to olfactory loss, especially among middle-age or older adults for whom xenobiotic exposure has accumulated over a longer time. Sourcing mainly from traffic exhaust and other fuel-burning operations, the smallest particulates, with aerodynamic diameter of less than 2.5μm (PM2.5), are among the most harmful forms of air pollution for human health.

We hypothesized higher exposure to common airborne pollutants to be associated with a faster rate of decline in olfactory identification ability. We tested this hypothesis using a well-characterized population-based sample with spatially detailed data of long-term exposure to air pollution (PM2.5 or NOx) and repeated olfactory identification tests across 12 years of follow-up. Participants showed significant decline in odor identification ability for each year in the study (β=-0.20). After adjustment for all covariates, residents of third (β=-0.09) and fourth (β=-0.07) exposure quartiles of PM2.5 had faster rates of olfactory decline than residents from the first quartile.

Our results suggest an association between air pollution exposure and subsequent olfactory decline. We speculate that cumulative effects of airborne pollutants on the olfactory system may be one underlying cause of olfactory impairment in aging.

Vascular calcification (VC) is a prominent clinical pathology of atherosclerosis, diabetes mellitus, hypertension, aging, and chronic kidney disease (CKD), resulting in abnormal calcium phosphate accumulation in the intimal and medial layers of the vessel wall. After vascular calcification, the stiffness of the vascular wall is increased, and the compliance is decreased, which results in myocardial ischemia, left ventricular hypertrophy, and heart failure. At present, vascular calcification is still lacks effective treatment methods, and the pathogenesis mechanism remains unclear.

The phenotype switching of vascular smooth muscle cells (VSMCs) has been regarded as the principal driver in the calcification of intimal and medial layers. VSMCs undergo the phenotypic transformation from a differentiated "contractile" into a dedifferentiated "synthetic" proliferative phenotype in the process of vascular calcification. The phenotypic switching VSMCs express higher osteoblast-like markers, and is associated with increased proliferation and migration ability. The osteoblast-like phenotype of VSMCs is regarded as the cellular characteristic factor of vascular calcification. Many factors such as oxidative stress damage, hyperphosphatemic environment, and inflammation increase the indices related to bone formation in VSMCs and promote their transformation into osteoblasts. On the other hand, a variety of biochemical factors are also involved in the phenotype switching of VSMCs.

Matrix vesicles (MVs), one kind of extracellular matrix derived extracellular vesicles (EVs), are membrane-bound microparticles released by cells, containing various cargo, including proteins, carbohydrates, lipids, DNA and small RNAs, such as microRNAs (miRNAs). The origin and composition of MVs determine their calcification potential. Recent evidence showed that extracellular MVs serve as nucleating foci to initiate microcalcification. The formation and secretion of MVs and the increase of intracellular alkaline phosphatase (ALP) activity are also involved in the osteoblast-like phenotype transformation of VSMCs.

However, the specific mechanisms and functions of MVs regulating vascular calcification have not been fully elucidated. For example, what is the originating cell that releases MVs in vascular calcification, and how do the pro-calcification MVs get into the recipient cell? This article aims to review the detailed role of MVs in the progression of VC and compare the difference with other major drivers of calcification, including aging, uremia, mechanical stress, oxidative stress, and inflammation. We will also bring attention to the novel findings in the isolation and characterization of MVs, and the therapeutic application of MVs in VC.