Doesn't the existence of mutational damage in nuclear DNA undermine the concept of nuclear backup copies as a solution to mitochondrial DNA damage? In fact engineering backup copies of the mutation-prone mitochondrial genes into the safe harbor of the nucleus is our strongest strategy for protecting the body from large mitochondrial deletion mutations. It's these deletions - particularly one that is found in so many cells that it is literally called "the common deletion" - that are most tightly linked to aging and diseases and disabilities of aging like Alzheimer's and Parkinson's diseases and the loss of functioning muscle fibers and strength with age. The concept of these engineered backup copies (technically, allotopic expression (AE)) was in fact the first of the proposed Strategies for Engineered Negligible Senescence (SENS) rejuvenation biotechnologies.

There are several things about the nature of the problem and the tools we have at our disposal that make AE not just viable but an enduring solution for mitochondrial mutations, even though nuclear DNA is also susceptible to free radical damage just like mitochondrial DNA is. The first is the sheer amount of oxidative damage in mitochondrial versus nuclear DNA. The mitochondrial DNA's exceptional vulnerability to free radical damage results, first and foremost, from its being located so close to the mitochondrial energy-production machinery, which is one of the major sources of free radical production in our bodies. We can now say with great confidence that the impact of mitochondrial free radicals on the nuclear DNA is negligible.

Even when mutations do occur in the nuclear DNA, the consequences are less likely to be harmful than those in the mitochondrial DNA. This is true in a couple of different senses. First, most mutations in the nuclear DNA are self-contained, causing defects in the proteins produced by one or a small number of genes that are directly damaged. By contrast, the "common deletion" mutation in mitochondrial DNA not only wipes out several genes that code directly for proteins, but also the genes that encode some of the machinery that the mitochondria need to assemble the proteins coded for by any gene in the mitochondrial genome. Without this machinery, the mitochondria can't produce any of the proteins encoded in the mitochondrial genome, including proteins whose genes are completely intact. There is no parallel catastrophic failure in garden-variety nuclear mutations.

A second way that mutations in the nuclear DNA are less likely to cause problems than mitochondrial DNA mutations derives from how much less of its nuclear DNA a given cell type needs to carry out its function. The mitochondrial DNA is a very lean operating system: almost every letter in its code carries essential instructions for producing some machinery that the mitochondria require for their function throughout life. By contrast, each cell houses lots of DNA in its nucleus that it can do without, or that can suffer a significant amount of mutation without harming the cell.

But still, our AE copies of mitochondrial genes are likely to suffer disabling mutations at some point in the future, even if that point is many times further away than anyone alive today has yet lived. Those mutations might even spread into tissue if they occur in stem cells. What can we anticipate our future options to fix the problem to be? The most obvious approach is a "simple" do-over: put another set of AE mitochondrial genes in the nucleus of our cells. A gene therapy given once can be given again.

The measurement of human ages, and by extension age-specific rates of any quantity, relies almost universally upon a single measurement system: the globally-incomplete paperwork-based system of documentary evidence known as vital registration. Despite age being the single most important risk factor for human health, along with gender, there has been no accurate and independently metric to validate human age measurements. If a developmentally mature person walks into a clinical setting with no paperwork, for example, there has been no independent or reproducible test available to measure their chronological age. As such, if age-based paperwork consistently records an incorrect age, there is no method by which that error can be detected because there is, or rather has been, no independently reproducible scientific method available for discovering such errors.

As a result, globally diverse document-based systems of vital registration are not subject to any document-independent technical validation or calibration. Systematic errors or error-generating processes that modify age records, from heavily biased or systemic errors to simple typographic mistakes, can therefore remain undetected indefinitely. Despite some scepticism on the reliability of age data this situation has been long ignored: first on the basis of an untestable assumption that such errors must be rare, and second on the seemingly reasonable statistical grounds that - if vital registration errors are assumed to be sufficiently rare and random - they may be safely ignored by fitting random error terms within a statistical model.

Recent theoretical work has shown that neither case seems to be a valid assumption especially at older ages. In survival processes, age-coding errors accumulate non-randomly with age - even when initial rates of error are vanishingly low, symmetrically distributed, and random - through a process that can substantially distort late-life data and massively inflate the frequency of errors at certain ages.

The underlying theoretical reason is simple. Consider, for example, a population of one million fifty-year-old people, into which a hundred 40-year-olds are accidentally included through age-coding errors: an initial error rate of 0.01% or one in every ten thousand. The paperwork of these 40-year-olds accidentally records them as aged 50 years - a surprisingly common mistake - and these 'young liar' errors appear, officially and on paper, as 50-year-olds. As the two cohorts age, the 'young liar' errors are less than half as likely to die as the actual 50-year-olds - because they are biologically 10 years younger - and errors therefore constitute a growing fraction of the population with age. In typical human populations, error rates will grow at an approximately exponential rate with age due to the better survival of 'young liars.' By age 85 more than half of the population becomes errors, by age 100 'young liar' errors constitute the entire population: a kind of error explosion caused by the asymmetrically better survival of 'young liars.'

Combined with the historical lack of paperwork-independent methods to validate and correct paper records, this simple theoretical process raises an uncomfortable possibility: that extreme age records may be dominated by undetected errors. Analysis of 236 nations or states across 51 years reveals that late-life survival data is dominated by anomalies at all scales and in all time periods. Life expectancy at age 100 and late-life survival from ages 80 to 100+, which we term centenarian attainment rate, is highest in a seemingly random assortment of states. The top 10 'blue zone' regions with the best survival to ages 100+ routinely includes Thailand, Kenya and Malawi - respectively now 212th and 202nd in the world for life expectancy, the non-self-governing territory of Western Sahara, and Puerto Rico where birth certificates are so unreliable they were recently declared invalid as a legal document. These anomalous rankings are conserved across long time periods and multiple non-overlapping cohorts, and do not seem to be sampling effects. Instead these patterns suggest a persistent inability, even for nation-states or global organisations, to detect or measure error rates in human age data, with troubling implications for epidemiology, demography, and medicine.

Age-related decline in skeletal muscle mass and function is a multifactorial phenomenon, characterized by the loss of muscle fibers and the atrophy of remaining fibers. Previous studies have highlighted the role of immune function changes in aging muscle, but the specific alterations in the immune microenvironment of skeletal muscle with age have yet to be fully understood. In this study, we utilized single nucleus RNA-seq analysis in combination with bulk RNA-seq to investigate the differences in cell composition and immune microenvironment between young and aged skeletal muscle tissue. Since macrophages were found to be the predominant immune cell population, we further identified a specific marker gene LYVE1 for macrophages and clustered them into subgroups. Additionally, we explored changes in cell-cell interactions between aged and young muscle. Furthermore, by analyzing bulk RNA-seq data, we examined the gene expression signature, functional differences, and infiltration characteristics of the young, aged, and sarcopenia groups, as well as the LYVE1-high and LYVE1-low groups.

Our analysis revealed that the sarcopenia group exhibited upregulation of several immune-related pathways, such as JAK-STAT, ERBB, and IL-2/IL-4 signaling pathways, in comparison to young controls. Previous studies have also linked these pro-inflammatory pathways to age-related muscle atrophy. We also discovered a crosstalk between immune cells and various non-immune cells within the muscle microenvironment. The results indicated that immune cells received signals from fibroblasts, endothelial cells, and other cell types, underscoring the significance of immune cells in the skeletal muscle microenvironment. Macrophages were found to be the predominant immune cell type in damaged muscles and played a crucial role in both the inflammation process and its resolution, contributing significantly to muscle repair. In response to anti-inflammatory cytokines, M1 macrophages transform into M2 macrophages in the later stages of skeletal muscle injury repair. Subsequently, these M2 macrophages along with resident M2 macrophages, facilitate the repair and regeneration processes by enhancing myoblast differentiation and vascularization, and stimulating fibro-adipogenic progenitor (FAP) cells to generate extracellular matrix. But macrophages in aged muscle are inclined to be polarized to a proinflammatory-phenotype, thereby negatively impacting the repair and regeneration capabilities of damaged muscle.

As the aging population has steadily expanded in recent decades, the incidence of Alzheimer's Disease (AD), Parkinson's Disease (PD), and stroke has continued to rise annually. Stem cells (SCs), a category of undifferentiated cells with the potential for diverse specialization, self-replication, and self-renewal, represent a promising strategy. However, stem cell application encounters significant limitations due to the quality control, immune incompatibility, safety evaluation, ethical considerations and logical considerations, and tumorigenicity.

Extracellular vesicles (EVs) are small bilayer lipid structures discharged by most eukaryotic cells and tissue types. Possessing structures and properties akin to cells, EVs present a distinctive advantage. SC-EVs differ from stem cells in that they neither replicate nor undergo uncontrolled division, which helps avoid issues related to the use of stem cells, such as the risk of tumor formation and the challenges of successful engraftment.

Importantly, SC-EVs possess the ability to cross the blood-brain barrier (BBB) to generate therapeutic impacts within the brain. In addition, SC-EVs enhance the longevity and availability of therapeutic cargo in EV-based nanocarriers compared to EVs derived from other cells, thanks to the immuno-regulating characteristics acquired from the parent cells. It has been also indicated that SC-EVs contribute to favorable outcomes, including extending therapeutic effects, stimulating the immune system, enhancing quality control, and maintaining long-term storage at -80°C. Furthermore, biomedical engineering technology can additionally optimize both the exterior and interior of SC-EVs, enabling them to target particular cells, enhance efficient BBB crossing, and attain specific therapeutic results. Inspiringly, the treatment efficacy of SC-EVs has been extensively explored in diverse neurological disorder models.

In this review, we summarize the methods of obtaining SC-EVs, including the isolation and differentiation of stem cells, and isolation and purification of extracellular vesicles. Then, we review the functions of native SC-EVs, including neuroprotection, angiogenesis, and preservation of BBB integrity, alleviation of neuroinflammation, and other functions. However, there are drawbacks including poor targeting efficiency, inconsistent therapeutic outcomes, and limited output efficiency, which can be solved by precondition, loading drug, and modified surface. Consequently, we summarize the strategies for the engineering of SC-EVs and their applications in AD, PD, and stroke. Ultimately, we outline the challenges linked to these extracellular vesicles in clinical translation and offer potential solutions.

Microvascular damage to the subcortical white matter is a major contributor to age-related dementia, including Alzheimer's disease (AD). Supplied by terminal arterioles with limited collateral flow from adjacent vascular territories, the subcortical white matter is particularly vulnerable to microvascular injury. Although vascular risk factors, such as hypertension and diabetes, are strongly linked to white matter lesions, accumulating evidence indicates that ApoE4, the leading genetic risk factor in sporadic AD, also increases the risk for cognitive impairment produced by vascular factors. Thus, ApoE4 carriers exhibit vascular pathology, microvascular alterations, and more white matter lesions linked to cognitive impairment.

ApoE4 is well known to be associated with alterations of the neurovasculature. ApoE4-positive individuals have dysregulated cerebral blood flow (CBF), as well as increased permeability of the blood-brain barrier (BBB) in the setting of AD. However, the cellular sources of ApoE4, the effector cells in the cerebral microvasculature and the signaling mechanisms driving the dysfunction remain unclear.

Although microglial cells reside in the brain parenchyma, border-associated macrophages (BAMs) seed the meninges, the choroid plexus and the space surrounding microvessels as they dive into the brain (perivascular space). BAMs are enriched with free radical-producing enzymes and, owing to their proximity to pial arterioles in the leptomeninges and to penetrating arterioles in the perivascular space, have recently emerged as a major cause of neurovascular dysfunction in animal models of neurodegeneration.

In the present study, we investigated the sources and targets of ApoE responsible for neurovascular dysfunction and the mechanisms of the effect. We found that ApoE4 acts on BAMs to alter critical cerebrovascular regulatory mechanisms through NADPH oxidase (NOX)-dependent production of reactive oxygen species (ROS). The dysfunction is abolished by BAM depletion or by genetic deletion of ApoE4 selectively in BAMs, identifying these cells as the sole source of the ApoE4 mediating the deleterious vascular effects.

Using a bone marrow (BM) transplantation strategy, we found that ApoE4-positive BAMs induce neurovascular dysfunction in ApoE3-TR mice, whereas ApoE3-positive BAMs rescue neurovascular dysfunction in ApoE4-TR mice, indicating that BAMs are also the main effectors of the dysfunction. Attesting to the pathogenic effect of BAM ApoE4 on white matter injury, ApoE4-positive BAMs enhance white matter damage and cognitive impairment in ApoE3-TR mice, whereas ApoE3-positive BAMs rescue this phenotype in ApoE4-TR mice. The findings establish BAMs as both sources and effectors of the ApoE4 acting on the cerebral microvasculature, unveiling a previously unappreciated cell-autonomous role of brain-resident macrophages in the neurovascular dysfunction and propensity of white matter injury associated with ApoE4.

It has recently been highlighted how a short healthy life-style program (LSP) can improve the functional outcomes of older people admitted to a Long-Term Care (LTC) facility. Although it is known that life-style medicine-based interventions can exert anti-aging effects through the modulation of oxidative stress and mitochondrial function, the mechanisms underlying the aforementioned effects have not been clarified, yet. For this reason, in this study, the outcomes were focused on the investigation of the possible mechanisms underlying the benefits of a short LSP in older people. This was achieved by examining circulating markers of oxidative stress and immunosenescence, such as Tymosin β (Tβ4), before and after LSP and the effects of plasma of older people undergone or not LSP on endothelial cells.

Fifty-four older people were divided into two groups (n = 27 each): subjects undergoing LSP and subjects not undergoing LSP (control). The LSP consisted of a combination of caloric restriction, physical activity, and psychological intervention and lasted 3 months. Plasma samples were taken before (T0) and after LSP (T1) and were used to measure thiobarbituric acid reactive substances (TBARS), 8-hydroxy-2-deoxyguanosine (8OHdG), 8-Isoprostanes (IsoP), glutathione (GSH), superoxide dismutase (SOD) activity and Tβ4. In addition, plasma was used to stimulate human vascular endothelial cells (HUVEC), which were examined for cell viability, mitochondrial membrane potential, reactive oxygen species (ROS), and mitochondrial ROS (MitoROS) release.

At T1, in LSP group we did not detect the increase of plasma TBARS and IsoP, which was observed in control. Also, plasma levels of 8OHdG were lower in LSP group vs control. In addition, LSP group only showed an increase of plasma GSH and SOD activity. Moreover, plasma levels of Tβ4 were more preserved in LSP group. Finally, at T1, in HUVEC treated with plasma from LSP group only we found an increase of the mitochondrial membrane potential and a reduction of ROS and MitoROS release in comparison with T0. The results of this study showed that a short LSP in older persons exerts antiaging effects by modulating oxidative stress at cellular levels.

Many studies have shown that longevity is regulated through cell non-autonomous signaling mechanisms by pathways originating in central nervous system neurons. These signaling pathways, which affect peripheral tissues, can significantly influence organismal health and longevity. Enhancement or suppression of these signaling pathways in central nervous system neurons leads to functional changes within the neurons (cell autonomous process) and transmits signals to the periphery to modulate its functions (cell non-autonomous process). For instance, in the nematode worm Caenorhabditis elegans, ASI amphid chemosensory neurons are important to maintain proper metabolic status, and possibly longevity. Ablation of ASI neurons completely suppresses the effect of lifespan extension induced by dietary restriction, suggesting that ASI neurons are required for the longevity effect of dietary restriction.

In the fly Drosophila melanogaster, neuronal activation of AMPK or Atg1, an autophagy-specific protein kinase, induces autophagy in the brain to slow aging and improves various parameters of healthspan. Drosophila insulin-like peptides are implicated in mediating the inter-tissue responses between the nervous system and the intestines. Furthermore, modifying mitochondrial function in neurons that influence aging and fly longevity also affects cells through cell non-autonomous mechanisms. A recent study demonstrated that the overexpression of hedgehog signaling, which is present in the glial cells of an adult fly, rescues proteostasis defects and the reduced lifespan in the glia of hedgehog mutant flies.

In mammals, increasing evidence highlights the role of the brain in the regulation of aging and longevity through cell non-autonomous signaling mechanisms. Specifically, the hypothalamus stands out as one of the most active regions involved in these signaling processes related to aging and longevity. In this review, we summarize the multiple signaling pathways in the hypothalamus that convey signals from the brain to peripheral organs and modulate aging and mammalian longevity. We describe how the structure and function of the hypothalamus are conserved across species and how these aspects are altered with age. Finally, we discuss some future perspectives on aging research that focus on the hypothalamus.

Osteoporosis and other metabolic bone diseases are prevalent in the aging population. While bone has the capacity to regenerate throughout life, bone formation rates decline with age and contribute to reduced bone density and strength. Identifying mechanisms and pathways that increase bone accrual in adults could prevent fractures and accelerate healing. G protein-gated inwardly rectifying K+ (GIRK) channels are key effectors of G protein-coupled receptor signaling. Girk3 was recently shown to regulate endochondral ossification. Here, we demonstrate that deletion of Girk3 increases bone mass after 18 weeks of age. Male 24-week-old Girk3-/- mice have greater trabecular bone mineral density and bone volume fraction than wildtype (WT) mice.

Osteoblast activity is moderately increased in 24-week-old Girk3-/- mice compared to WT mice. In vitro, Girk3-/- bone marrow stromal cells (BMSCs) are more proliferative than WT BMSCs. Calvarial osteoblasts and BMSCs from Girk3-/- mice are also more osteogenic than WT cells, with altered expression of genes that regulate the wingless-related integration site (Wnt) family. Wnt inhibition via Dickkopf-1 (Dkk1) or β-catenin inhibition via XAV939 prevents enhanced mineralization, but not proliferation, in Girk3-/- BMSCs and slows these processes in WT cells. Finally, selective ablation of Girk3 from osteoblasts and osteocytes is sufficient to increase bone mass and bone strength in male mice at 24 weeks of age. Taken together, these data demonstrate that Girk3 regulates progenitor cell proliferation, osteoblast differentiation, and bone mass accrual in adult male mice.

We analyzed data from 2,105 participants to the 1999-2002 National Health and Nutrition Examination Survey aged ≥50 years old who were followed for mortality through 2019. Epigenetic age accelerations (EAAs) were calculated from Horvath, Hannum, SkinBlood, Pheno, Zhang, Lin, Weidner, Vidal-Bralo and Grim epigenetic clocks regressed on chronological age. Using cox proportional hazards regression, we estimated the hazard ratio (HR) for the association of EAA (per 5-year) and the DunedinPoAm pace of aging (per 10% increase) with overall, cardiovascular, and cancer mortality, adjusting for covariates and white blood cell composition.

During a median follow-up of 17.5 years, 998 deaths occurred, including 272 from cardiovascular disease and 209 from cancer. Overall mortality was most significantly predicted by Grim EAA (HR: 1.50) followed by Hannum (HR: 1.16), Pheno (R: 1.13), Horvath (HR: 1.13) and Vidal-Bralo (HR: 1.13) EAAs. Grim EAA predicted cardiovascular mortality (HR: 1.55), whereas Hannum (HR: 1.24), Horvath (HR: 1.18) and Grim (HR: 1.37) EAAs predicted cancer mortality. DunedinPoAm pace of aging was associated with overall (HR: 1.23) and cardiovascular (HR: 1.25) mortality.

Working memory function is a critical cognitive ability that deteriorates with age following adulthood. Beyond its well-studied role in sensorimotor control, rhythmic neural activity in the beta band (15 to 25 Hz) has been suggested to regulate the status of working memory contents. Dynamics in beta-band activity reflect working memory processing. There is a decrease in beta activity when information needs to be maintained and an increase when information needs to be deleted. Maintenance-related beta decrease is primarily observed in the prefrontal cortex. By contrast, post-response beta increase is observed among task-related networks involving frontal and centroparietal regions, facilitating removal of both memory contents and associated representations such as motor plans after responses. Specifically, neurophysiological evidence from nonhuman primates demonstrated localized post-response beta increase at sites containing memory information during the time course of working memory clear-out. Whether such dynamics can be observed in human electrophysiology and how these neural dynamics change with age is unknown.

We adopted a novel approach to assess between- and within-group differences across ages. We combined cross-trial variability, which has largely been studied with broad-band EEG signal and fMRI hemodynamic responses, with rhythmic dynamics in the beta range, and examined them during both working memory maintenance and post-response deletion phases. Our novel analytical approach suggests that, when considering cross-trial fluctuations of beta power, variability explains individual differences in working memory performance during distinct phases for each age group.

Whereas individual memory performance of younger adults was explained by frontal beta variability during maintenance, memory performance of older adults was primarily explained by post-response beta variability. Thus, task-related cross-trial variability augments individual state-dependent characteristics and predicts behavioral differences within and across age groups. With the age-related dissociations between maintenance and post-response phases, beta variability may serve as an age-related, task-sensitive signature of individual differences in distinctive working memory computations.

"One known feature of Parkinson's is cell death resulting from aggregates of the alpha-synuclein protein. The protein begins to aggregate about 15 years before symptoms appear, and cells begin to die 5-10 years before diagnosis is possible with the means available today. This means that we have an extensive time window of up to 20 years for diagnosis and prevention, before symptoms appear. If we can identify the process at an early stage, in people who are 30, 40, or 50 years old, we may be able to prevent further protein aggregation and cell death."

Past studies have shown that alpha-synuclein aggregates form in other parts of the body as well, such as the skin and digestive system. In the current work the researchers examined skin biopsies from 7 people with and 7 people without Parkinson's disease. "We examined the samples using super-resolution imaging, combined with advanced computational analysis - enabling us to map the aggregates and distribution of alpha-synuclein molecules. As expected, we found more protein aggregates in people with Parkinson's compared to people without the disease. We also identified damage to nerve cells in the skin, in areas with a large concentration of the pathological protein. In future studies we will increase the number of samples and develop a machine learning algorithm to spot relatively young individuals at risk for Parkinson's."

Amyloid-beta and tau proteins have long been associated with Alzheimer's disease. Researchers recruited 104 people with a family history of Alzheimer's. They scanned the participants' brains using a combination of positron emission tomography (PET) to detect the presence and location of the proteins and magnetoencephalography (MEG) to record brain activity in these regions. The scientists compared the results of the two scans and found that brain areas with increased levels of amyloid-beta showed macroscopic expressions of brain hyperactivity, reflected by increased fast- and decreased slow-frequency brain activity. For people with both amyloid-beta and tau in their brain, the pattern shifted towards hypoactivity, with higher levels of pathology leading to brain activity slowing.

Using cognitive tests, the team discovered that participants with higher rates of this amyloid-tau related brain slowing showed higher levels of decline in attention and memory. The findings suggest that the interplay between amyloid-beta and tau lead to altered brain activity before noticeable cognitive symptoms appear. In a follow up study, researchers plans to rescan the same participants over time to prove whether the accumulation of the two proteins promotes further slowing of brain activity, and whether this accurately predicts the cognitive evolution of the participants.

Progressive neurodegenerative diseases affect a significant proportion of the population; in a single year, there are as many as 276 million disabilities and 9 million deaths as a result of neurological diseases. Mitochondrial function, aging, and neurodegenerative processes appear to be intricately linked; central nervous system degeneration is a major feature of loss-of-function mitochondrial diseases, involving mutation of nuclear DNA or mitochondrial DNA. Meanwhile, mitochondrial dysfunction occurs during healthy aging and is further associated with several neurological diseases, including Alzheimer's disease (AD), Huntington's disease, Friedreich's ataxia, multiple sclerosis, motor neuron disease, Parkinson's disease (PD), and vanishing white matter disease (VWMD).

Aging increases neurodegenerative risk factors and processes, including progressively impaired cognitive and/or motor function due to cellular dysfunction, senescence, and/or neuronal death. Furthermore, impaired mitochondrial respiration, biogenesis, mitophagy, and axonal transport can be causative factors in dysfunctional protein synthesis, folding, aggregation, and trafficking, as well as inflammation, oxidative stress, and genomic instability. Thus, targeting mitochondrial function offers the premise of mitigating cellular degeneration. Furthermore, the cumulative impact of oxidative damage is exacerbated by the inherent susceptibility of mitochondrial DNA to reactive oxygen species (ROS)-induced mutations. Consequently, neurons appear to have an inherent susceptibility to mitochondrial dysfunction.

The interrelated nature of mitochondrial dysfunction and the inherent impact of energy dysregulation in cellular stress, proteotoxicity, and cell death implies that mitochondrial therapeutics may be beneficial for multiple neurodegenerative diseases and aging, i.e., to treat degeneration as a secondary mitochondrial disease. In an age of emerging gene and cell-based therapies, further research is warranted to explore the most effective mitochondrial-based strategies to slow neurodegenerative disease progression and aging.

The retrospective study looked at people with type 2 diabetes who started diabetes medication from 2014 to 2019 in South Korea. People taking SGLT2 inhibitors were matched with people taking other oral diabetes drugs, so the two groups had people with similar ages, other health conditions and complications from diabetes. Then researchers followed the participants to see whether they developed dementia or Parkinson's disease. Those taking the SGLT2 inhibitors were followed for an average of two years and those taking the other drugs were followed for an average of four years.

Among the 358,862 participants with an average age of 58, a total of 6,837 people developed dementia or Parkinson's disease during the study. For Alzheimer's disease, the incidence rate for people taking SGLT2 inhibitors was 39.7 cases per 10,000 person-years, compared to 63.7 cases for those taking other diabetes drugs. Person-years represent both the number of people in the study and the amount of time each person spends in the study. For vascular dementia, which is dementia caused by vascular disease, the incidence rate for people taking the SGLT2 drugs was 10.6 cases per 10,000, compared to 18.7 for those taking the other drugs. For Parkinson's disease, the incidence rate for those taking the SGLT2 drugs was 9.3 cases per 10,000, compared to 13.7 for those taking the other drugs.

After researchers adjusted for other factors that could affect the risk of dementia or Parkinson's disease, such as complications from diabetes and medications, they found that SGLT2 inhibitor use was associated with a 20% reduced risk of Alzheimer's disease and a 20% reduced risk of Parkinson's disease. Those taking the drugs had a 30% reduced risk of developing vascular dementia.

Despite the significance of biological wrinkle structures, much of the research in this area has relied on animal models including fruit flies, mice, and chickens, due to limitations in replicating wrinkle formation in vitro. As a result, the detailed processes behind wrinkle formation in living tissue remain largely unknown. Researchers addressed this limitation by developing an epithelial tissue model composed solely of human epithelial cells and extracellular matrix (ECM). By combining this model with a device capable of applying precise compressive forces, they successfully recreated and observed wrinkle structures in vitro that are typically seen in the gut, skin, and other tissues in vivo. This breakthrough allowed them, for the first time, to replicate both the hierarchical deformation of a single deep wrinkle caused by a strong compressive force and the formation of numerous small wrinkles under lighter compression.

The team also discovered that factors such as the porous structure of the underlying ECM, dehydration, and the compressive force applied to the epithelial layer are crucial to the wrinkle formation process. Their experiments revealed that compressive forces deforming the epithelial cell layer caused mechanical instability within the ECM layer, resulting in the formation of wrinkles. Additionally, they found that dehydration of the ECM layer was a key factor in the wrinkle formation process. These observations closely mirrored the effects seen in aging skin where dehydration of the underlying tissue layer leads to wrinkle development, providing a mechanobiological model for understanding wrinkle formation.