April As the macula prevebtion the eye progressively Pharmaceutical-grade ingredient compliance, so does a person's ability Age-reoated see objects clearly in the center Ailmsnts his Diuretic herbs for detoxification of vision, though peripheral vision is usually preserved. National Academies of Science, Engineering, and Medicine. Thanks for your feedback! For older adults and their families, effective health care requires quality communication with and among health care professionals. If you are a Mayo Clinic patient, this could include protected health information.

Age-related ailments prevention -

Desai said the discovery provides potential treatment strategies to head off inflammatory cascades that lie at the heart of many cardiometabolic and neurodegenerative diseases.

Macrophages are white blood cells that play critical roles in the immune system and good health. They swallow up dead or dying cells, allowing the removal of cellular debris, and they patrol for pathogens and other foreign invaders. In this latter role, they act as important sentries for the immune system, calling for help from other immune cells as needed.

Scientists have known that macrophages become less effective with age, but it has been unclear why. These changes, the scientists believe, make the macrophages prone to chronic, low-grade inflammation at the best of times.

And when the immune cells are confronted by an invader or tissue damage, they can become hyperactive. Further, the UVA Health scientists suspect that the mechanism they have discovered will hold true not just for macrophages, but for many other related immune cells generated in the bone marrow.

That means we may be able to stimulate the proper functioning of those cells as well, potentially giving our immune systems a big boost in old age, when we become more susceptible to disease.

The researchers have published their findings in the scientific journal Nature Aging. The article is open-access, meaning it is free to read. The research team consisted of Seegren, Logan R. Harper, Taylor K. Downs, Xiao-Yu Zhao, Shivapriya B.

Viswanathan, Marta E. Stremska, Rachel J. Olson, Joel Kennedy, Sarah E. Ewald, Pankaj Kumar and Desai. The scientists reported that they have no financial interests in the work. The research was supported by the National Institutes of Health, grants AI, GM, GM, P30 CA and T32 GM, and by the Owens Family Foundation.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog. Older adults need to be physically active in order to stay healthy and independent. Physical activity can help prevent heart disease, cancer, stroke, and diabetes.

It can also help prevent falls and fractures. It is important to understand how much physical activity you need. Good nutrition, especially in combination with regular physical activity, is key to maintaining a healthy weight and reducing your risk of cancer, heart disease and diabetes.

As you get older, it is important to understand how your nutrition needs change. If you are over 60 years old and have a low income, the Senior Farmers Market Nutrition Program may help you get fresh fruits and vegetables. It's never too late to quit smoking! No matter how old you are or how long you have been smoking, by quitting you can significantly lessen your risk of smoking-related illness and death.

It is also important to avoid secondhand smoke. Call Washington's confidential and toll-free Tobacco Quitline for support: QUIT-NOW Calcium can help to keep your bones strong and healthy to prevent fractures. The current recommendations are for men and women over age 50 to get mg of calcium and IUs of vitamin D each day.

Vitamin D allows the body use calcium properly. To help with getting enough calcium, read food labels when you go shopping.

Many people enjoy the opportunity to get more involved in their community as they get older and volunteering can be a great way to improve your wellbeing, make friends and help others.

Depression is not a natural result of aging, and it can happen to anyone at any age. DSHS offers resources that can help older adults recover from depression. If you are depressed, you may feel more tired, experience increased pain or have an overwhelming sense of sadness. If you or someone you know is thinking about suicide, call the hour toll-free National Suicide Prevention Lifeline for help: Take care of yourself by managing chronic conditions that impact your health.

Working with your healthcare provider and participating in educational opportunities are great ways to ensure that you stay as active and independent as possible. If you are a caregiver for a spouse or family member with a chronic condition, DSHS Caregiver Support is available to help.

Falls are not a normal part of aging, and they can be prevented. There are simple steps you can take to improve safety in your home and practice balance exercises that will decrease your risk of being injured by falling. Age-related hearing loss can increase your risk of falls and contribute to problems with thinking and memory.

If you or your loved ones notice that you are having more difficulty with hearing, have your hearing checked by an Audiologist. You can take a brief quiz on the National Institutes of Health website to see if you might be experiencing hearing loss. For resources in Washington State, visit this website for the Office of the Deaf and Hard of Hearing.

Drinking too much alcohol can lead to serious health problems or injuries. Most men should limit their use to two drinks per day. Most women should limit their use to one drink per day.

One drink equals: one beer 12 oz , or one glass of wine 5 oz , or one shot of proof hard liquor 1.

Make healthy choices— Age-related ailments prevention fruits, vegetables, whole grains, lean meats, low-fat dairy products, ailmentss water. Being active can ailmennts Pharmaceutical-grade ingredient compliance prevent, delay, and manage chronic diseases; preventino balance and stamina; Pharmaceutical-grade ingredient compliance risk Agw-related falls; and Protecting cellular DNA from mutations brain health. TIP Ailmejts for moderate physical activity, like walking, at least minutes a week minutes a day and muscle strengthening activity, like carrying groceries, at least 2 days a week. If you use tobacco, take the first step towards quitting by calling QUIT-NOW for FREE help. This can prevent disease or find it early, when treatment is more effective. Share your family health history with your doctor, who can help you take steps to prevent chronic diseases or catch them early.

Age-related ailments prevention -

Telomeric DNA shortens with increasing numbers of cell divisions, and when it shortens to the Hayflick limit, telomere dysfunction causes a DNA damage response.

This, in turn, induces cell cycle arrest and proinflammatory factor expression, ultimately leading to organismal aging. A telomere is a nuclear protein structure formed by telomeric DNA and binding proteins.

Numerous studies have confirmed that telomere length is inversely proportional to age. Telomerase activity is highest in human embryonic tissues and decreases progressively with age.

Epigenetics refers to changes in phenotype or gene expression caused by mechanisms other than changes in DNA sequence. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factors to DNA.

This clock measures our biological age and predicts our lifespan. This clock confirmed the intrinsic links between the epigenetic clock and some aging mechanisms, such as the activation of proinflammatory and interferon pathways, transcriptional and translational mechanisms, and the DNA damage response.

showed that epigenetic clocks can provide insight into the aging process of the human brain and predict the risk of dementia. identified a blood-DNA-methylation measure, DunedinPoAm, a method that estimates the rate of aging in subjects in the years prior to the measurement.

Histone modifications include several different types: acetylation, methylation, phosphorylation, ubiquitination, glycosylation, ADP-ribosylation, deamination, and proline isomerization.

Histone acetyltransferases are usually transcriptionally activators, and histone deacetylases exert transcriptional repression functions. Epigenetic studies have confirmed the widespread loss of histones and local and global remodeling of chromatin with age. elegans after mitochondrial stress occurs.

Chromatin accessibility is also a common feature of active regulatory elements, including enhancers, promoters, insulators, and chromatin-binding factors, to which transcription factors can be recruited by DNA-specific interactions. Single-stranded RNAs ssRNAs, including short ncRNAs small interfering RNAs siRNAs , microRNAs miRNAs , circular RNAs circRNAs , PIWI-interacting RNAs piRNAs , endogenous siRNAs endo-siRNAs , and long ncRNAs lncRNAs mainly function as probes, antisense AS probes, miRNA analogs, and miRNA inhibitors and have great potential for gene therapy and molecular diagnosis.

reported that this derepression results in an elevation in the level of intracellular dsRNA, which activates innate immune responses and induces the neuroinflammation found in nearly all age-related neurodegenerative diseases.

Aging and various neurodegenerative diseases e. This prevents the peptides from folding prematurely and helps them fold into the correct shape. The endoplasmic reticulum ER initiates the unfolded protein response UPR , which contributes to protein degradation and selective translation.

reported that loss of ATF4 diminishes hematopoietic stem cell HSC function with an aging-like phenotype and impairs leukemogenesis by targeting HIF1α and p16 Ink4a. Koyuncu S et al.

have reported that ubiquitin-coding gene expression is not downregulated in aged wild nematodes. This finding suggests that differences in ubiquitination levels are not due to differences in ubiquitin-protein expression but rather are due to loss of ubiquitination modifications.

Instead, SUMO modification increases stability. In addition, ribosomes have been shown to play an important regulatory role in proteostasis. This change leads to ribosome-associated quality control overload and de novo peptide aggregation, thus exacerbating protein aggregation.

Among the molecular changes associated with aging, alterations in autophagy have become recognized as important features of aging in different species. There is increasing evidence that autophagic activity decreases with age in different tissues in different species.

elegans is associated with increased expression of the autophagy genes ATG-1, ATG-7, and ATG Recently, researchers found much higher levels of transition metals e. Iron and copper accumulate in senescent cells.

In senescent cells, iron accumulation is due to defective autophagic degradation of ferritin by lysosomes. In addition, in aging cells, FTMT accumulates on the outer membranes of defective mitochondria and promotes mitophagy by specifically interacting with the autophagic cargo receptor NCOA4 coupled to the LC3-II double-membrane phagophore.

Furthermore, in senescent cells, reductions in the levels of Atp7a a copper exporter block autophagic—lysosomal degradation of copper. Atp7a copper transporter copper-transporting ATPase 1, Ctr1 copper transporter 1, FTMT mitochondrial ferritin, LC3 I cytosolic form of LC3, LC3-II LC3-phosphatidylethanolamine conjugate, mtROS mitochondrial ROS, MVB multivesicular body, NCOA4 nuclear receptor coactivator 4, TFR transferrin receptor.

With aging, mitochondria become highly susceptible to morphological changes. These changes result in reduced function due to oxygen radical damage, which eventually causes the aging of the organism. Mitochondria are major sources of ROS. elegans , starvation or heat stress or exercise stimulation increases RST, and increasing RST improves Redox-stress response capacity RRC and health span, suggesting that increasing RST values through early stimulation can effectively delay aging.

performed an in-depth analysis of the cysteine oxidation networks, the Oximouse dataset, a dataset that quantifies the percentage of reversible modifications at approximately , cysteine sites in ten tissues of young and aged mice.

Aging-related mutations in mtDNA cause defects in mitochondrial oxidative phosphorylation OXPHOS functions. It is suggested that the supplement of NAD precursors alone does not improve the insulin sensitivity, mitochondrial respiration, energy metabolism, ectopic lipid accumulation, and plasma inflammatory markers of healthy overweight or obese individuals, which may be due to the insufficient supplement time and dose of NAD, resulting in the limited improvement of metabolism in overweight people.

Mitochondrial quality control is an important factor in the maintenance of mitochondrial function that mainly includes the biogenesis of mitochondria and the biodegradation of damaged mitochondria. The above results suggest that the dynamic balance between mitochondrial biogenesis and degradation is essential for mitochondrial quality control.

Cellular senescence can be divided into two categories: replicative senescence and stress-induced premature senescence. This results in cell proliferation stagnation and loss of differentiation ability. Elderly individuals often present with chronic low-grade inflammation, which is collectively referred to as immune aging.

Premature T-cell failure may accelerate aging in multiple organs and systems, with thymic degeneration, mitochondrial dysfunction, genetic and epigenetic alterations, and imbalance in protein homeostasis being the four main hallmarks of T-cell senescence. reported that in mice with mitochondrial transcription factor A TFAM deletion, T cells with mitochondrial dysfunction induce a variety of aging-related phenotypes, such as metabolic disorders, cognitive impairment, and cardiovascular diseases, which ultimately lead to the premature death of mice.

Stem cells, with their potential for self-renewal and multidirectional differentiation, are core components of regenerative medicine. They have been used in the treatment of a variety of diseases, including hematopoietic, central nervous system, and immune system disorders.

Activation of autophagy can alleviate the aging of bone marrow MSCs and restore osteogenic differentiation and proliferation in senescent bone marrow MSCs. Theodore T. Ho et al. found that hematopoietic stem cells HSCs that are unable to undergo cellular autophagy have a buildup of mitochondria and are in a constant state of metabolic activation, which accelerates the differentiation of myeloid cells through abnormal DNA modifications, ultimately affecting the ability of HSCs to self-enhance.

Murine and human HSCs enlarge during the aging process, which may result in reduced proliferation and altered metabolism and may ultimately reduce stem cell function.

Intercellular communication is typically characterized by the release of soluble factors and affects the function of neighboring cells. Senescent cells also communicate with each other and with neighboring cells in a cell-to-cell or proximal-secretory manner.

The somatotrophic axis is a neuroendocrine axis consisting of relevant hormones and receptors on the hypothalamus—pituitary—target organs that plays an important role in nutrient sensing and cellular energy perception.

The human microbiota contains multiple symbiotic microorganisms and participates in nutrient sensing. Aging is the result of a combination of physical, environmental, and social factors, so elaborating the molecular mechanisms that trigger aging is a daunting task.

Human lifespan is closely related to the reduction of tissue and organ repair and regenerative potential. Specifically, at the molecular, cellular and systematic levels, genetic, epigenetic, and environmental regulatory factors cause a reduction in the physiological reserve of the organism in response to stress through complex molecular mechanisms that work together to promote aging.

Molecular mechanisms e. Overall, these mechanisms stunt cell proliferation, alter metabolism and gene expression patterns and induce high levels of ROS production, maintaining the cellular senescent phenotype. Although the number of early senescent cells is not large, they can limit the regenerative capacity of tissue stem cells and induce the accumulation of cellular damage thereby promoting age-related diseases.

Current developments in high-throughput genomics, proteomics, and metabolomics allow the characterization and quantification of thousands of epigenetic markers, transcripts, proteins and metabolites, and can reveal the overall changes that occur with age in complex organisms at the molecular level.

Therefore, the integration of these molecular markers and related molecular mechanisms into a comprehensive assessment of biological age to counteract age-related functional decline and morbidity is increasingly becoming a hot issue of interest for scientists. Aging is the most important risk factor for aging-related diseases.

Therefore, the increasing age of the world population is accompanied by increases in the occurrence of various aging-related diseases. These diseases include neurodegenerative diseases, cardiovascular diseases, metabolic diseases, etc. These diseases place a great burden on the social economy and the public health system.

Next, we will focus on the regulatory mechanisms of aging and the pathogeneses of aging-related diseases. AD is a progressive neurological disorder that causes problems with memory, thinking and behavior in elderly individuals.

AD commonly occurs in individuals 60 years of age and older. Additionally, the hyperphosphorylation of tau proteins leads to the formation of senile plaques, which lead to impaired memory and reduced cognitive function.

DNA mutations and defects in DNA repair mechanisms are important causes of AD. When DNA damage exceeds the repair capacity, mistranslation by DNA polymerase can lead to the development of neurodegenerative diseases.

This leads to enhanced cellular oxidative stress and increased inflammatory responses. These processes trigger aging-related neurodegeneration and promote neuron senescence and AD.

Epigenetic modifications, such as DNA methylation, PARylation, ubiquitination, and acetylation, also play important regulatory roles in AD progression.

Neurons cannot proliferate and are sensitive to epigenetic modifications caused by aging. This leads to DNA damage, which may be responsible for neurodegeneration. Phosphorylation or hyperphosphorylation of histone H3 and deacetylation of histone H4 can be detected in the hippocampi of early AD patients.

These findings suggest that epigenetic factors play an important role in the occurrence of AD. An increase in misfolded proteins and aggregation of tau proteins are also involved in the development of AD. Aβ oligomerization may block synaptic plasticity and signal transduction.

These effects result in neuronal hyperexcitability, susceptibility to excitotoxicity and metabolic exhaustion, ultimately resulting in Aβ neurotoxicity.

Further research has revealed that these nerve cells have autophagy disorders and cannot effectively decompose Aβ, leading to the corresponding phenotype.

Tau proteins may also aggregate and form neurofibrillary tangles. These pathological tau conformations can recruit native tau proteins, induce the formation of more abnormally folded tau proteins, and further promote pathological fibrillar aggregation. Decreased mitochondrial quality and activity are associated with normal aging, neuronal mitochondrial dysfunction and energy deficits during AD development and promote Aβ and tau pathology.

Research in animal and cellular models of AD and in patients with sporadic late-onset AD suggests that impaired mitophagy triggers Aβ and tau accumulation through increased oxidative damage and cellular energy deficit, leading to synaptic dysfunction and cognitive deficits.

These changes in turn impair mitophagy. Neurons require high levels of ATP to perform their physiological functions, so mitochondrial dysfunction also contributes to the development of AD.

In addition, AD mainly manifests as a large group of SASPs caused by abnormal secretion of growth factors, cytokines, ROS and metalloproteinases. Astrocytes are the largest population of glial cells in the brain and are involved in various physiological functions of the central nervous system.

Senescent astrocytes exhibit decreased normal physiological function and increased secretion of SASP factors that contribute to Aβ accumulation, tau hyperphosphorylation, neurofibrillary tangle deposition, and neurological deficits in AD.

The disruption of astrocyte functions may lead to a chronic inflammatory response and central nervous system pathologies, including impaired synaptic plasticity, BBB dysfunction, glutamate excitotoxicity, and a decrease in the number and proliferation of neural stem cells, leading to the development of neurodegenerative diseases such as AD.

PD is a chronic and progressive neurodegenerative disease with movement disorder in elderly individuals. Due to striatal dopamine deficiency, PD presents with dyskinesias, including impaired range and speed of movement, limb stiffness, or resting tremors.

In PD patients, α-syn aggregation is widely regarded as a major causative factor. α-Syn oligomers form large, insoluble, neurotoxic fibrils called Lewy bodies.

α-Syn oligomers can spread from cell-to-cell throughout the brain, thereby aggravating the progression of PD.

Many studies have found that older PD patients have more severe impairment of dopamine function and higher levels of α-syn and tau proteins in the cerebrospinal fluid than younger people. To date, ~20 genetic mutations have been associated with PD, including missense mutations in SNCA α-syn , PARK7, and LRRK2 and missense mutations or loss-of-function mutations in PINK1, PRKN, PLOG, and GBA.

Neuroinflammation has been an important target of drug intervention in neurodegenerative diseases. Increased numbers of senescent cells in PD patients are associated with increased SA-β-gal and p16 activity and sporadic α-syn deposition, leading to increased production of the proinflammatory cytokine interleukin-6 IL In addition to glial cells, fibrillar α-syn increases IL-1β secretion by interacting with TLR2, which is associated with NLRP3 inflammasome activation.

Currently, over 64 million patients worldwide have HF, and HF is a growing area of interest. Studies have suggested that cardiac aging is a critical risk factor for impaired cardiac function and the progression of HF.

Thus, senescent cardiomyocytes can promote inflammation and dysfunction. The SASP of senescent cardiomyocytes promotes HF progression. Therapies targeting the SASP could therefore also be used to treat HF-related pathologies.

Research has indicated that oxidative stress plays a major role in the pathophysiology of cardiomyocyte senescence, hypertrophic remodeling and HF. These processes are strongly associated with severe cardiac dysfunction and HF progression.

The heart is a well-recognized organ with extremely active energy metabolism. Due to the inefficiency of the heart in storing ATP, cardiomyocytes must continuously generate ATP. Recent studies have suggested that cardiomyocyte senescence could have major adverse effects on multiple aspects of energy metabolism, reduce the heart rate and result in HF.

However, miR could regulate the metabolism of the failing myocardium by altering the Sirtuin 3 Sirt3 expression and the mitochondrial protein acetylation. Additionally, it causes the senescent phenotype in cardiomyocytes during aging.

Epigenetic alterations have also been increasingly recognized as major contributors to the initiation and progression of cardiomyocyte senescence and HF. For example, recent studies have shown that overexpression of the histone demethylase KDM4D in cardiomyocytes through upregulation of genes involved in proliferation and the cell cycle can delay cell cycle exit and profoundly promote cardiomyocyte proliferation.

For instance, fibroblast growth factor 20 reduces pathological cardiac hypertrophy by activating the signaling pathway of the deacetylase SIRT1, inducing deacetylation of FOXO1 and reducing oxidative stress. In addition to senescent cardiomyocytes, senescent nonmyocytes in the heart, such as endothelial cells, can also be observed in HF.

These conditions could lead to systolic and diastolic dysfunction and thereby drive HF. Moreover, the senescence-associated hallmarks of endothelial cells, including p53 acetylation and senescence-associated β-galactosidase SA-β-gal activity, are significantly upregulated.

In addition, a study has shown that in atrial appendages of patients undergoing cardiac procedures, increased levels of endothelial nitric oxide synthase can promote many cardiovascular phenotypes, including atrial fibrillation, during endothelial cell dysfunction.

Similarly, multiple types of chemotherapeutic agents, including anthracyclines, can result in the senescence of many types of cells in the heart in the clinical management of cancer.

This effect is achieved via the induction of severe DNA damage and cardiac mitochondrial dysfunction in cells, which ultimately leads to HF.

For example, SIRT1 mRNA and protein levels are decreased, and the activation of AMPK is inhibited. This, in turn, enhances inflammatory stimulation in doxorubicin-induced senescent vascular smooth muscle cells VSMCs.

Vascular aging refers to aging-induced structural and functional changes that occur in the vasculature. Dysfunction of the vasculature contributes to aging-related diseases such as atherosclerosis, giant cell arteritis and AD, and is one of the leading causes of morbidity and mortality in elderly individuals.

Endothelial cells tightly regulate vasodilation by secreting vasoactive substances and growth factors. Senescent endothelial cells can be observed in atherosclerosis. The increased production of endothelin-1 and decreased production of nitric oxide in senescent endothelial cells lead to vascular inflammation and impaired vasodilation, compromise vascular endothelial integrity, and lead to vascular aging and atherosclerosis.

Therefore, the accumulation of senescent endothelial cells can lead to vascular dysfunction, and vice versa. Oxidative stress is one of the main mechanisms driving atherosclerosis. Endothelial senescence can be triggered by oxidative stress or vascular inflammation.

Nuclear factor E2-related factor 2 Nrf2 is a key transcription factor that regulates hundreds of antioxidant genes and cytoprotective genes.

Studies have shown that Nrf2 function is defective in atherosclerosis, hypertension and HF, and these conditions increase oxidative stress and accelerate aging.

Epigenetic changes, such as miRNA binding or histone acetylation, also contribute to endothelial cell senescence. An increasing amount of evidence suggests that miRNAs play important roles in the pathogenesis of vascular aging and atherosclerosis, and identification of aging-related miRNAs may provide opportunities for the treatment of cardiovascular disease.

These aging-related exosomes may become biomarkers for some aging-related diseases and provide new targets for the treatment of these diseases in the future. In addition, the levels of SIRT1 and SIRT6, protein deacetylases that play key roles in regulating DNA damage repair, maintaining telomere length and metabolic homeostasis, are decreased in atherosclerosis.

Metabolic factors such as hyperuricemia and dysregulation of the renin—angiotensin system can also promote endothelial cell senescence. Prohibitin-1 is highly expressed in endothelial cells. This protein is mainly located in the inner mitochondrial membrane and plays important roles in mitochondrial biogenesis and the maintenance of mitochondrial function.

This suggests that prohibitin-1 is involved in cardiovascular disease. Klotho expression is reduced in mouse models of premature aging, which results in the development of atherosclerosis and greatly shortens lifespan. However, overexpression of Klotho prolongs lifespan.

Similar to endothelial cell senescence, VSMC senescence also contributes to atherosclerosis. Studies have shown that both p16 and p21 expression and SA-β-gal activity are increased in plaque VSMCs. For example, sustained DNA damage signaling promotes the secretion of pro-osteogenic cytokines, leading to VSMC senescence, mineralization, and subsequent vascular calcification.

This, in turn, leads to telomeric DNA damage and VSMC senescence. These cytokines promote the recruitment of monocytes, macrophages and lymphocytes, thereby accelerating the risks of plaque growth and rupture.

Patients with this syndrome suffer from severe atherosclerosis, which accelerates aging and causes premature death. Immune system functions decline with increasing age, and a decline in immune function is a major risk factor for some cardiovascular and neurodegenerative diseases.

Blood vessels are special sites for the immune system. Blood vessels consist of endothelial cells, VSMCs, macrophages, dendritic cells, fibroblasts and pericytes.

Thus, the senescence of multiple cells can affect vascular homeostasis. Increased proportions of Th17 and regulatory T cells are observed in atherosclerotic plaques. Circulating endothelial progenitor cells EPCs are generated in the bone marrow and are important for maintaining endothelial integrity.

T2DM is a global health problem, especially for older adults. This disease is characterized by defective insulin secretion, hyperglycemia and hyperlipidemia. The incidence of T2DM is growing rapidly for people over the age of Pancreatic β-cells secrete insulin and maintain the balance of blood glucose and lipids.

The senescence of β-cells leads to β-cell dysfunction, which impairs insulin secretion and the homeostasis of glucose and lipid metabolism. The expression of p16 INK4a and the number of senescent β-cells are increased in pancreatic islets. Elevated levels of plasma free fatty acids FFAs and glucose result in inflammatory factor and ROS accumulation, ER stress and mitochondrial dysfunction, which impair the proliferation of β-cells and adipose cells.

Circulating FFAs and glucose activate the TLR4-MyD 8 pathway and stimulate the production of proinflammatory factors and chemokines in β-cells, such as IL-1β, IL-6, IL-8, CCL2, and CXCL1. In the islets of T2DM patients, macrophage infiltration is increased. These macrophages are prone to polarize toward the proinflammatory M1 type.

Insulin resistance is a major factor for the pathogenesis of T2DM, which accelerates β-cell senescence. In one T2DM animal model, senescent cells accumulated, proliferation was diminished, and the levels of senescence markers were increased in β-cells and adipose cells. These findings suggest that β-cell and adipose cell senescence might be associated with insufficient insulin secretion and the pathogenesis of T2DM.

Conditioned medium from β-gal-positive cells increases the expression of p16 in healthy β-cells. Aside from β-cells, adipose tissue is the most important energy reservoir and endocrine organ, and it regulates the homeostasis of lipid and glucose metabolism. Many factors can lead to the senescence of adipose cells, such as telomere attrition, DNA damage, mitochondrial dysfunction, ROS, ER stress and inflammation.

Adipose tissue contains a large number of immune cells, which are affected by different physiological environments, lifestyle factors, caloric intake and aging. Adipose cell senescence triggers inflammation and insulin resistance in other metabolic organs, which lead to T2DM.

NAFLD has been linked to aging-related chronic liver disease, and the major characteristic of NAFLD is hepatocellular fat accumulation. NASH is associated with inflammation and fibrosis and can further progress to advanced cirrhosis and even hepatocellular carcinoma.

Although the pathogenesis of NASH is not fully understood, lipotoxicity, oxidative stress, apoptosis, and inflammation have been suggested to promote the progression from NAFL to NASH.

Genetic and epigenetic changes affect the pathogenesis of NAFLD. Genomic studies have reported that multiple single-nucleotide polymorphism SNPs are independently associated with the development and progression of NAFLD.

In a cohort of individuals from the UK and Finland, the rs variant within CDKN1A was found to be significantly associated with the progression of NAFLD. Loomba et al. found that a set of differentially methylated CpG islands in the peripheral blood-DNA of NASH patients correlate with the severity of hepatic fibrosis and that this DNA methylation signature is associated with the age-related acceleration of NASH in patients.

Impairment of mitochondrial function is a major factor that contributes to NAFLD. Mitochondrial dysfunction has been linked to a reduction in fatty acid β-oxidation FAO that is due to decreased carnitine palmitoyl transferase-1 CPT-1 activity and decreased fatty acid clearance, resulting in the pathogenesis of NAFL.

During NAFLD, the impairment of FAO inhibits the activity of PPARα, resulting in hepatic lipid accumulation and inflammation. The increased ROS levels may cause further FAO damage, which aggregates hepatic steatosis. These experiments have also demonstrated that these effects are SIRT2- and irisin-dependent.

Chronic ER stress and UPR signaling play a major role in the aging process and are involved in NAFLD. These pathways induce inflammatory reactions and hepatocyte apoptosis and promote NASH progression. One study has verified that Creld2 deficiency results in dysregulation of the UPR and causes NASH during ER stress conditions in male mice.

Autophagic function declines with increasing age. Lipophagy is a process of macroautophagy in which lipid droplets are selected for autophagic degradation. Both autophagic and CMA activity are impaired with aging, leading to lipid accumulation in various organs, including the liver.

With aging, impairment of hepatic autophagy in the fatty liver may fail to remove damaged mitochondria, therefore leading to activation of the mitochondrial death pathway and causing NASH via oxidative stress and apoptosis.

In general, the liver has a remarkable capacity for regeneration and restoration. However, age-mediated changes impair the hepatic regenerative capacity. Senescent hepatocytes exhibit telomere attrition, which correlates with the progression of NAFLD.

Senescence markers p16, p21, and p53 have been identified in hepatocytes of NAFLD, and hepatocyte senescence correlates with the progression of NAFLD. However, the levels of CDK4 in NAFLD patients are increased in an age-dependent manner.

Seventy percent of the blood that the liver receives is supplied from the intestine via the portal vein; thus, bacteria-derived molecules influence hepatic metabolism and the pathogenesis and progression of NAFLD through enterohepatic circulation.

Advanced NAFLD patients exhibit significant dysbiosis with increased abundances of Bacteroides, Escherichia, and Ruminococcus and a decreased abundance of Prevotella bacteria. When microbial products reach the liver via the portal vein, toll-like receptors TLRs and nucleotide-binding oligomerization domain-like receptors NLRs in both parenchymal and nonparenchymal cells can be activated and trigger the innate immune system.

Under insulin-resistant conditions, the amounts of nonesterified fatty acids NEFAs in the circulation that are derived from white adipose tissue lipolysis increase, resulting in fat overload in the liver.

Interestingly, under conditions of NAFLD-related hepatic insulin resistance, hepatic DNL remains activated in the absence of hepatic gluconeogenesis inhibition. Activated ChREBP stimulates the glycolytic pathway, leading to an increase in the metabolic precursors for DNL.

However, NAFLD further worsens hepatic and systemic insulin resistance. Human studies have revealed that there is a positive association between the number of macrophages and NAFLD severity. Hepatic macrophages include both resident macrophages Kupffer cells KCs and infiltrating monocyte-derived macrophages.

These cytokines induce inflammation and promote monocyte infiltration into the liver. Further studies have shown that the self-renewal of resident KCs is impaired in NASH mice and that monocyte-derived KCs are generated to maintain KC numbers.

This suggests that the cellular stress signature probably drives both the death of resident KCs and the generation of monocyte-derived KCs. Therefore, aging-related hepatic fat metabolic imbalance results in NAFL.

Hepatic accumulation of lipids induces mitochondrial dysfunction and ER stress and further causes oxidative stress, hepatocytic senescence, inflammation, and fibrosis.

These factors lead to the progression of NAFLD. Insulin resistance and dysbiosis of the gut microbiota accelerate the development and progression of NAFLD. Impaired hepatic lipid metabolism and inflammation further worsen insulin resistance and dysbiosis of the gut microbiota and promote the progression of atherosclerosis Fig.

Crosstalk between aging and NAFLD in aging-related metabolic disease. Aging is related to impaired insulin sensitivity. Under insulin-resistant conditions, the amount of NEFAs in the circulation that are derived from white adipose tissue lipolysis increases, resulting in fat overload in the liver.

Aging-related impairment of autophagy and mitochondrial dysfunction reduce hepatic lipid droplet breakdown and fatty acid β-oxidation, respectively.

Moreover, under conditions of aging-related obesity, hepatic DNL increases due to ChREBP pathway activation. These disorders of lipid metabolism result in the pathogenesis of NAFL. Following hepatic lipid metabolic impairment and lipid accumulation, lipotoxicity and ER stress are induced, and mitochondrial function further worsens, leading to oxidative stress, hepatocyte apoptosis, hepatocyte senescence and inflammation and thus promoting the progression of NASH.

Senescent hepatocytes secrete proinflammatory cytokines IL-6, IL-8, TNF-α, and IL-1β that stimulate resident KCs in the liver. Activated KCs present M1-like proinflammatory activity and secrete cytokines to induce monocyte infiltration into the liver and differentiation into macrophages.

Furthermore, impaired resident KCs can induce monocyte differentiation into monocyte-derived KCs to maintain the KC pool in the liver. Both resident KCs and monocyte-derived KCs interact with HSCs and activate HSCs to produce collagen.

In addition, dysbiosis of the gut microbiota impairs intestinal permeability; thus, bacteria-derived molecules enter the liver via the portal vein and in turn influence hepatic metabolism and the progression of NAFLD.

However, hepatic metabolic impairment and inflammation further worsen insulin resistance and dysbiosis of the gut microbiota. Moreover, hepatic lipid metabolic disorder results in hypercholesterolemia and hypertriglyceridemia, leading to accelerated progression of atherosclerosis.

com , licensed under a Creative Commons Attribution 3. OA is a chronic inflammation-related disease characterized by joint pain, cartilage loss, and joint inflammation.

Cartilage loss is an important pathological feature of OA. Chondrocyte senescence is one of the major risk factors leading to OA. Chondrocytes maintain the stability of the joint synovium by synthesizing or degrading extracellular matrix components, such as type 2 collagen and proteoglycan polymers.

With the development of OA, chondrocytes begin to degrade collagen and proteoglycans by secreting matrix metalloproteinase MMP 13 and ADAMTS-5, which ultimately leads to cartilage calcification. Telomere attrition is associated with the pathogenesis of OA. This leads to apoptosis and an inflammatory response.

Mitochondrial dysfunction in chondrocytes is also related to the pathogenesis of OA. In the chondrocytes of OA patients, the numbers of mitochondria are decreased, and the integrity of the mitochondrial membrane is impaired.

Inflammation promotes metabolic reprogramming of chondrocytes in which glycolysis is upregulated and OXPHOS is downregulated. This leads to cartilage degeneration and chondrocyte senescence. Metabolic reprogramming also leads to mitochondrial dysfunction.

Thus, they can maintain homeostasis and participate in the pathogenesis of OA. The SASP recruits macrophages to infiltrate the synovium and activate the inflammatory response, which leads to synovitis.

OP is an aging-related bone disease that is characterized by bone mass reduction and bone microstructure damage. With aging, the anabolic pathway bone formation is downregulated, and the absorption pathway bone resorption is upregulated.

Aging-related bone loss is caused by a reduction in the number of osteoblasts. Genomic instability is a hallmark of aging, which also leads to aging-related bone mass loss. An abnormal DNA repair system accelerates cell senescence.

In humans, abnormal DNA repair systems lead to progeria, which is characterized by abnormal bones and low bone mass. This causes an imbalance between bone remodeling and bone loss.

The expression level of p16 is elevated in B cells, T cells, myoid cells, osteoprogenitors, osteoblasts and osteoclasts of month-old mice. SASP factors in the supernatant of senescent cell culture can promote the survival of osteoclast progenitor cells and inhibit osteoblast differentiation. MSCs located in the bone marrow and spongy bone are responsible for maintaining the balance of bone resorption and formation.

Depletion of bone marrow MSCs is one of the main causes of OP in the elderly population. COPD is a lung disease characterized by the presence of chronic bronchitis or emphysema that leads to the development of airflow limitations. The incidence rate of COPD is high in elderly individuals, especially those above the age of 65 years.

Age is one of the main risk factors for COPD. The structural and physiological characteristics between aged lungs and COPD lungs overlap to a considerable extent; such characteristics include increases in the size of alveoli and end-expiratory lung volume without destruction to the alveolar wall.

The senescence of functional cells and the exhaustion of progenitor cell groups in aged lungs lead to a decline in lung function that is closely related to the progression of COPD.

Basal cells are multipotent progenitors located in the conducting airway that can differentiate into club cells and further differentiate into ciliated cells or secretory cells goblet cells, etc. Research has shown that the numbers of basal and club cells decrease with age. Alveolar type 2 cells form the main progenitor cell group of the lung parenchyma and can differentiate into alveolar type 1 cells.

Although the number of alveolar type 2 cells remains unchanged, the self-renewal and differentiation capacity of these cells decrease. During aging, the concentration of alveolar macrophages AMs in the respiratory tract declines, and phagocytosis and the scavenging capacity are impaired.

This triggers nonspecific inflammatory reactions that recruit neutrophils and dendritic cells to inflammatory sites. Insufficient clearance leads to an aggravated inflammatory response. Increases in the levels of proinflammatory cytokines, such as IL-6, are associated with increased COPD obstruction and increased risks of COPD-related complications.

Autophagy alterations contribute to COPD. In the COPD mouse model, the activity of TFEB, the main transcriptional regulator of autophagy and lysosomal biogenesis, is inhibited. Many studies have shown that mitochondrial dysfunction accelerates COPD.

In the airways, the lungs and blood of COPD patients show mitochondrial morphological alterations, mitochondrial dysfunction, and increased ROS levels.

The levels of PARK2 protein are decreased in COPD lungs and are positively correlated with lung function. PINK1- and PARK2-deficient mice show mitochondrial dysfunction and a COPD phenotype.

Epigenetic alterations also play a role in the process of COPD. Abnormal DNA methylation has been detected in small airways and lymphocytes in COPD patients. These reduced levels fail to control downstream transcription factors, such as FoxO3 and Nrf2, resulting in an abnormal immune response.

The mTOR signaling pathway is highly activated in multiple cells in COPD lungs, which enhances the susceptibility to pulmonary inflammation and emphysema. Increased genomic instability and telomere dysfunction are associated with COPD. In COPD patients, the levels of DNA damage markers in lung tissue and peripheral blood cells are increased, , telomeres are shortened, , and the expression of DNA repair-related proteins is decreased, all of which are related to disease severity.

BPH is a common urogenital disease in middle-aged and elderly men. Previous studies have indicated that increasing age is an important risk factor for the development of BPH. At present, the pathogenesis of BPH is believed to include upregulation of androgen receptor expression, increased levels of inflammation-promoting growth factors, metabolic syndrome, endocrine and neurotransmitter changes caused by oxidative stress and epithelial—mesenchymal interactions, and lifestyle and dietary habits.

All of these mechanisms can lead to the proliferation and apoptosis of epithelial cells and stromal cells in prostate tissue. These effects result in an increase in the number of cells and eventually lead to the development of BPH.

Changes in androgen levels and tissue remodeling caused by aging are generally considered to be the major determinants of BPH. There is clinical evidence that taking a 5α-reductase inhibitor can reduce the concentration of dihydrotestosterone in prostate tissue, thereby preventing the further development of BPH.

Compared with controls, androgen-depleted animals have lower bacterial counts and inflammation, reducing the risk of BPH development. Recent research also suggests that BPH may be an immune-inflammatory disease. These factors further lead to abnormal remodeling of the prostate structure characterized by tissue injury, chronic immune responses, and fibromuscular growth.

Autoimmune responses associated with T cells may induce abnormal proliferation of epithelial and stromal cells involved in epithelial—mesenchymal transition EMT. Both epithelial and stromal cells of the prostate can upregulate proinflammatory signals and trigger an inflammatory response following a bacterial challenge.

As inflammation progresses, macrophages and MCP1, IL-8, IL-1, transforming growth factor-β2, and C-C motif chemokine 3 accumulate locally. This accumulation can increase the rate of cell growth, aggravate inflammation, and promote the development of BPH.

A key to the development of BPH in elderly individuals is metabolic syndrome, which is associated with low testosterone and hyperestrogenism. The characteristics of metabolic syndrome include T2DM, hypertension, obesity, high insulin levels, and low high-density lipoprotein-cholesterol levels.

Metabolic syndrome components alone are risk factors for the development of BPH. IGF-1 has been shown to have strong mitogenic and antiapoptotic effects on prostate tissue.

These effects suggest that early interventions that improve the insulin level may help control BPH. AMD is a degenerative disease of the macula that leads to severe visual loss in the elderly population.

In the retina, senescence of the RPE, neurons, microglia, and endothelial cells accelerates AMD. Aging of the immune system decreases inflammatory regulation ability and immune clearance.

Senescent phagocytes such as macrophages and neutrophils show reduced phagocytic activity and clearance and induce the production of atypical lipid species in the retina.

A variety of immune cells, such as monocytes, neutrophils and T cells, invade the retina. Retina-derived SASP induces BRB matrix degradation, destroys the tight junction proteins of the retinal barrier, recruits and activates immune cells to increase inflammation or releases angiogenic growth factors and VEGF to participate in angiogenesis.

Senescent cells also show abnormal metabolic regulation. For example, senescent macrophages show abnormal ABCA1-mediated cholesterol metabolism, which reduces drusen clearance and promotes retinal aging.

Autophagy and protein homeostasis affects AMD progression. The expression of autophagy-related proteins and autophagy flux are decreased in the retinas of aged rats and AMD patients. Mitochondrial dysfunction is also associated with AMD progression.

The RPE in elderly individuals and AMD patients shows a decrease in the number of mitochondria and impaired activity. In addition, the shift from OXPHOS to glycolysis causes RPE dysfunction and subsequent photoreceptor death. Humanin enhances mitochondrial function and biogenesis via increases in mtDNA mass, mitochondrial number, and the protein expression level of the mitochondrial transcription factor mtTFA, which is a key protein involved in mitochondrial biogenesis.

In addition, mtDNA and nuclear DNA damage, , telomere dysfunction, methylation changes[46], and RPE stem cell senescence contribute to AMD progression.

Presbycusis, also referred to as aging-related hearing loss ARHL , is a progressive form of sensorineural hearing loss that occurs with aging and is a common condition in the elderly population. Accumulation of dysfunctional mitochondria might promote presbycusis progression.

Aging destroys protein homeostasis in the inner ear and leads to alterations in ion and water homeostasis that result in ARHL-specific dysfunction Autophagy alterations contribute to AMD.

During the senescence of SGNs in SAMP8 mice, lc3-II is upregulated with lipofuscin accumulation. Recently, BCL-2 interacting protein 3-like Bnip3 and NIX knockout in mice was shown to promote presbycusis by downregulating mitophagy. The role of inflammation in ARHL has attracted much attention.

Increased genomic instability is associated with the onset of presbycusis. Mice expressing error-prone mtDNA polymerase gamma PolgDA or with POLGD knockout show defective mtDNA replication fidelity and premature aging, which leads to early-onset ARHL.

Epigenetic factors are also involved in the process of presbycusis. Altered methylation modifications of connexin, amino acid transporter and signaling pathway-related proteins contribute to the risks of presbycusis in different populations. The link between aging and cancer is complex.

Although there is clear evidence that cells entering a senescent state can act as a barrier to tumorigenesis, some studies have demonstrated that, in certain conditions, persistent senescent cells can acquire pro-tumorigenic properties.

Senescent cells can initiate both intrinsic and extrinsic mechanisms to inhibit tumorigenesis. Induction of stable growth arrest forms a natural barrier to tumorigenesis which works as a typical intrinsic antitumor manner. In Oncogene-induced senescence, aberrant activation of proto-oncogenes such as RAS fuels unscheduled DNA replication, causing malignant cellular growth.

In turn, cells trigger firm proliferative arrest and senescence by initiating key cell cycle arrest genes such as TP53, p16INK4a, and p21, which counteract malignant growth.

Senescent cells promote senescence or death of neighboring cells through direct cell-cell interactions or inflammatory SASP factors release, causing increased production of ROS and a sustained DNA damage response, thereby also limiting the proliferation of neighboring precancerous or cancerous cells.

that drive macrophages, lymphocytes and NK cells to recruit to tumor sites, which activate immune surveillance. Chromatin reader bromodomain-containing protein 4, PP21 axis, and NFκB signaling pathway regulate immune surveillance by regulating the expression and type of SASP. However, studies in the past decade also proved established that the persistent senescent cells induce pro-tumorigenic effects by producing a proinflammatory and immunosuppressive microenvironment.

SASP factors secreted by senescent cells include pro-proliferation factors such as IL-6 and IL-8, tissue angiogenic remodeling factors such as VEGF and CXCL5, , and pro-cancer metastasis and invasion factors such as MMPs and GDF SASP factors-driven immunosuppression is also responsible for the pro-tumorigenic effects of senescent cells.

In the therapy-induced senescence model, cells undergoing senescence regain proliferative properties through reversibility of senescence, or acquire senescence-associated stemness by reprogramming mechanisms and turn into highly aggressive tumors, which drive tumor recurrence and progression.

Senescence has dual roles in tumorigenesis. Whether senescent cells exert tumor-suppressive or tumor-promoting effects depends on numerous factors: the triggers of senescence, the number and persistence of senescent cells, the type and period of tumor tissue, the immune status of the body, and the status of key senescence proteins such as TP Despite recent advances in understanding the biology of senescence in cancer, the process of targeting senescence for cancer prevention and treatment still faces many challenges.

Overall, the existing evidence indicates that the hallmarks of aging are the common drivers of aging-related diseases. However, the diverse aging-related diseases in different organs and systems have their own combinations of molecular hallmarks of aging.

Mitochondrial dysfunction Fig. Moreover, numerous aging-related diseases are associated with a chronic inflammatory status, which is frequently attributable to the long-term accumulation of senescent cells in various tissues.

Other hallmarks of aging, such as genomic instability, epigenetic alteration, telomere attrition, deregulation of nutrient sensing, and dysbiosis of the gut microbiota, are also related to many major aging-related diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, and chronic respiratory diseases.

Therefore, intricate mechanisms underlie different aging-related diseases. Understanding the common and different mechanisms will provide new insights to aid in the development of therapeutic strategies against aging-related diseases. Mitochondrial dysfunction contributes to diverse aging-related diseases.

With aging, an increase in ROS production in mitochondria leads to oxidative stress, causing oxidative damage to DNA especially mtDNA , lipids, and proteins. An increased mtDNA mutation rate causes increased frequencies of errors or mutations in mtDNA-encoded enzyme subunits, resulting in impaired OXPHOS.

mtDNA is released into the cytoplasm or outside the cell and participates in SASP secretion by activating cGAS-STING pathways.

Reduced mitochondrial biogenesis mediated by PGC1 and NRF decreases the number of newborn mitochondria. The mitophagy defects and mitochondrial dysfunction trigger Aβ and tau accumulation, leading to synaptic dysfunction and cognitive deficits during AD development.

The metabolic transition from OXPHOS to glycolysis leads to altered metabolite generation. Mitochondrial pathway-mediated apoptosis is an important form of cell death. Mitochondrial dysfunction contributes to AD, HF, diabetes, OP, OA, presbycusis, NAFLD, COPD, AMD, and atherosclerosis by inducing oxidative stress, inflammation, apoptosis, and metabolic alterations.

SASP related to various age-related diseases. Senescent cells that have a proinflammatory SASP can cause substantial pathogenic effects, resulting in various aging-related diseases. In the tissue microenvironment, the SASP involves chemokines, cytokines, proteases, and growth factors, which have a range of negative effects on neighboring cells, the surrounding extracellular matrix and other structural components.

Senescent cells exhibit increased expression of chemokines, such as CCL2 and MCP1, which promotes the recruitment of monocytes, macrophages and lymphocytes in the vascular endothelium, islets, liver, synovium, and retinas. The accumulation of proinflammatory factors, such as IL-6, IL-1β, TNF-α, and IL-8, exacerbates the pathogenesis of various age-related diseases.

Proteases destroy the external BRB and cartilage by inducing matrix degradation in AMD and OA. Growth factors, such as TGF-β and IGF-1, induce the abnormal proliferation of epithelial and stromal cells involved in EMT in BPH. The multifaceted SASP of senescent cells promotes the progression of various diseases and may be a therapeutic target.

Molecular mechanisms for proteostasis in aging-related diseases. Aging, genetic mutations, environmental and lifestyle insults, and various other stresses cause increases in the amounts of unfolded, misfolded, and oxidized proteins, which lead to activation of the protein degradation system of the UPS and lysosomal proteolysis including nonselective autophagy and selective autophagy, such as mitophagy and reticulophagy.

Chaperones help refold unfolded proteins and assist in the formation of autophagosomes and ubiquitin-proteasomes. Balanced proteostasis leads to healthy aging and longevity.

Disrupted proteostasis induces protein aggregation, cellular organelle function loss, increased ROS production and chronic inflammation, which lead to the development of many aging-related diseases. Aging is an inevitable pathophysiological process caused by many factors that lead to a progressive reduction in the ability to resist stress and contribute to a variety of aging-related diseases.

Healthy longevity without aging-related diseases has been pursued by humans since ancient times. The prevention and treatment of aging-related diseases is promising but challenging. However, there are many mechanisms of aging, and there are also differences in the development of different aging-related diseases.

There are nondrug therapies for aging-related disease prevention and treatment, such as CR, nutrition, exercise, and intestinal microbiota transplantation, as well as drug therapies targeting different aging mechanisms and symptoms of aging-related diseases Fig.

Next, this review will focus on the advances in laboratory and clinical studies on these interventions and treatments in the contexts of different aging-related diseases. Possible interventions and treatments against aging-related diseases.

Proof-of-principle therapeutic strategies used in cell experiments, animal experiments, and clinical trials are shown together. Daily lifestyle changes, such as exercise, dietary interventions, and weight loss, can inhibit aging and reduce the occurrence and development of aging-related diseases, subsequently promoting healthy aging and longevity.

Drug therapy is the main strategy targeting aging. Antiaging drugs exert their effects by reducing the number of senescent cells, alleviating the SASP, and exerting anti-inflammatory and antioxidant effects while affecting multiple signaling pathways.

Altering the metabolism or composition of the gut microbiota with drugs or through microbiota transplantation can also inhibit aging and aging-related diseases. Moreover, cell replacement therapy, cell transplantation, gene therapy and immunotherapy can be used to promote healthy aging and longevity and to treat aging-related diseases.

Before the clinical signs and symptoms of AD appear, lifestyle interventions, including good nutrition and physical exercise, can improve the cognitive status of individuals and attenuate both the development and progression of AD.

In addition, long-chain fatty acids, including omega-3 polyunsaturated fatty acids, eicosapentaenoic acid, and docosahexaenoic acid, has been found to be beneficial for cognitive and mental health. These fatty acids can delay aging-related cognitive potential decline as well as AD.

In terms of drug targets, neurodegenerative diseases share common features of protein aggregation, such as neurofibrillary tangles and Lewy bodies.

A common strategy for AD treatment is to clear Aβ through the application of the amyloid cascade hypothesis. However, the long-term effects of these drugs still need to be verified, and results have differed among the existing clinical trials.

In recent years, there has been an increasing emphasis on strategies involving nonamyloid targets for the treatment of AD, including therapeutic approaches to combat inflammation and oxidative stress; to provide synaptic and neuronal protection; to affect vascular factors; to provide mitochondrial protection; and to intervene at the epigenetic level.

Two typical examples of repurposed drugs are escitalopram and metformin. Several clinical studies on the use of aducanumab for mild cognitive impairment and mild AD in patients started in The EMERGE trial showed that high-dose aducanumab can slow the progression of clinical cognitive impairment.

However, another clinical trial, ENGAGE, did not find a significant protective effect. Therefore, this clinical trial evidence is contradictory, and more phase III studies are needed to determine the efficacy of aducanumab in the future.

At present, cholinesterase inhibitors, such as tacrine and donepezil, are primarily used clinically to relieve the symptoms of AD. However, with increasing age and the aggravation of symptoms, the number of active neurons decreases, which makes it difficult for drugs to effectively treat AD.

The main currently approved drugs are cholinesterase inhibitors acetylcholinesterase inhibitors and N-methyl-D-aspartate NMDA receptor antagonists. Acetylcholinesterase inhibitors generally reduce the hydrolysis of acetylcholine released from presynaptic neurons into the synaptic cleft by inhibiting acetylcholinesterase in the synaptic cleft.

These effects enhance the stimulation of cholinergic receptors and improve cognitive function in patients with mild to moderate disease. A number of researchers have proposed mechanistic links among oxidative stress, inflammation, and neurodegeneration; therefore, the use of natural plant components and dietary antioxidants to prevent neuronal damage may be a therapeutic approach to reduce AD risk.

In traditional Chinese medicine, many natural herbs have been indicated to be effective alternative treatments for AD, such as Astragalus, Artemisia, Ginseng, Ginkgo polygonatum , Chuanxiong, and Lycium barbarum. Decreased removal of dysfunctional mitochondria is an important mechanism of AD.

The development of strategies to treat this impairment of mitophagy would benefit from the screening and identification of new mitophagy regulators. They found two effective compounds, kaempferol and rhapontigenin, that increased glutamatergic and cholinergic neuron survival and function, eliminated Aβ and tau lesions, and improved memory in animals.

Recent studies have found that gut microbes are key regulators of many diseases and that gut microbes are involved in neurodegeneration through the gut microbiota—brain axis. This finding supports the possibility of new microbiota-based therapeutic options. Although many studies have found a possible relationship between the gut microbiota and AD pathogenesis, the inconsistency and reproducibility of existing clinical results need to be addressed before clinical application.

There is increasing evidence that the Mediterranean diet, which includes high amounts of fruits, vegetables, whole grains, fish, and unsaturated fatty acids, reduces the incidence of PD. The prevention of microglial activation represents a potential therapeutic strategy.

With the development of science and technology, cell transplantation and gene therapy have brought good prospects to the treatment of PD.

However, both are in the experimental stage and have not been used in clinical practice. Notably, transplantation of human induced pluripotent stem cells into primate dopaminergic neurons has been found to lead to the formation of dense neurites in the striatum. Nondrug treatments for PD include surgical treatments that can relieve the clinical symptoms, such as deep brain stimulation and rehabilitation and exercise therapy.

Targeting specific posttranslationally modified forms of α-syn, such as the phosphorylated, nitrated, oxidized or truncated forms, may also be a strategy for PD therapy.

Masitinib is a novel tyrosine kinase inhibitor that targets the proliferation and activation of mast cells and microglia, reducing the risk of motor nerve injury.

Gastrointestinal dysfunction is also an important pathogenic mechanism during the development of PD. In PD, a highly complex relationship between the gut microbiota and the brain, including the vagus nerve and α-Syn in the enteric nervous system, alters gut permeability and inflammation.

Additionally, it causes changes in gut microbes and their metabolic activity. However, the results from studies on the link between exposure to certain types of oral antibiotics and an increased risk of PD are inconsistent and still controversial.

Moreover, there are also differences in the results of existing animal experiments and human experiments regarding the therapeutic efficacy of FMT. Aging can lead to decreased cardiac function and HF. Antiaging strategies can reduce the progression of HF.

For example, drugs that delay cellular senescence and adoption of healthy lifestyles smoking cessation, physical exercise, dietary interventions, and weight control could be effective.

However, CR could exert an extensive and unfavorable influence on aging-associated diseases such as nervous system diseases, cardiac diseases and cancer. Additionally, recommendation of one specific diet over another is difficult because of the limited available evidence.

This treatment improves the quality of life and is well tolerated in patients with chronic HF with preserved ejection fraction. This inhibitor can improve left ventricular systolic function and conduction velocity, and suppress myocardial fibrosis and cardiac hypertrophy in mice with Ang II-induced HF.

Cycloastragenol, a major natural compound in Astragalus membranaceus , has been shown to have multiple pharmacological effects, such as antiaging, anti-inflammatory and antifibrotic effects.

Cycloastragenol is also the only telomerase activator discovered to date that can delay telomere shortening by inducing telomerase expression. Cell replacement therapy is a new strategy for HF that is aimed at improving function by replacing dysfunctional cells with sufficient differentiated human stem cells.

Li, J. et al. Moreover, MSC-based cardiac regenerative treatment may be a novel therapeutic approach. However, the potential cytotoxicity to host cells should be considered when choosing MSC-based cell interventions.

These strategies to enhance cardiac cells may further stimulate paracrine effects, and this needs to be taken into account in cardiac regeneration medicine. Currently, there are multiple strategies for cardiac regeneration under active development, each with its own advantages and challenges.

In the future, new developments will be necessary to achieve cardiac regeneration. For example, stimulating endogenous cardiac regeneration by mobilizing and modulating resident stem cells is actually the targeting step in most current strategies for cardiac regeneration.

Future research and clinical application should also aim to enhance the regeneration capacity of endogenous resident cardiac endothelial cells to promote therapeutic neovasculogenesis in the injured heart.

However, both intrinsic and extrinsic regulators need to be taken into account when designing therapeutic strategies to enhance the regeneration of the injured heart. For example, the immunological activity of cells can engage in complex interactions with resident heart cells and the extracellular matrix of tissue, ultimately leading to cell death in the heart.

Aging-induced alterations in gut microbial composition and metabolism are associated with the development of HF. Since the launch of the Human Microbiome Project, intestinal microecology research has developed rapidly, providing new directions for studying the mechanisms of drug action in HF.

With regard to deregulated nutrient sensing, studies have shown that interventions affecting the gut microbiota or its related enzymes can regulate intestinal microbial metabolism and reduce circulating trimethylamine oxide TMAO levels.

Thus, they can treat HF and improve outcomes in HF patients. These findings support the use of dietary polyphenols for the treatment of HF through microbiota modulation. Patients with atherosclerosis should change their lifestyle, control their total intake of calories, and reduce the proportion of fat, especially saturated fat, in their total caloric intake.

In many cases, diet is the main driver, because dietary interventions can reduce ROS production, reduce nuclear DNA and mtDNA damage accumulation, and maintain mitochondrial homeostasis.

Over the past few decades, epidemiological, clinical andbasic studies have demonstrated that dietary interventions are key strategies to inhibit aging, promote health and prevent atherosclerosis. The Mediterranean diet can prevent atherosclerosis by interfering with multiple signaling pathways that promote the development of the disease.

The Mediterranean diet has beneficial effects on blood lipids, lipoprotein particles, inflammation, oxidative stress and the expression of proatherosclerotic genes.

Therefore, this diet can reduce the incidence of multiple aging-related diseases, such as cardiovascular disease, neurodegenerative disease and metabolic disease. Senolytics are standard antiaging treatments that are designed to identify and target senescent cells.

Common drugs in this class include dasatinib and quercetin. Moreover, the SASP of senescent cells promotes senescence of the secreting cells and other cells. Therefore, preventing the secretory behavior of senescent cells and eliminating the deleterious effects of intercellular communication can also combat cellular senescence.

This idea has resulted in the development of novel antiaging drugs called senomorphics, which are represented by metformin. Metformin is commonly used to treat diabetes and affects longevity through AMPK activation.

Apps linked to a phone or device can assist with medication management. And remote sensors and artificial intelligence can be integrated to facilitate care of older adults, including those with dementia, and may also help older adults remain comfortably within their own homes as they age.

Build on our understanding of the roles of nutrition, obesity, sleep, and metabolic status to develop more effective health maintenance strategies. Epidemiological studies — and, in some cases, studies in animals — have shown clear positive effects of lifestyle choices such as healthy diet and physical activity, as well as the negative effects of obesity, malnutrition, and less-than-optimal sleep patterns on health and age-related morbidity.

We will use these and other findings to launch clinical trials of dietary and other behavioral measures and adherence strategies for the prevention or delay of disease and disability.

Support research on mechanisms of behavior change in midlife and older age. Behavior change is difficult, yet adherence to healthy lifestyles can reduce the risk of disease and increase healthspan.

Having a better understanding of how and why successful behavior change occurs is the key to providing blueprints for effective and efficient behavior interventions that could reliably improve health outcomes.

We will support research on the behavioral, psychological, interpersonal, and neurobiological mechanisms that drive healthy behavior change to inform the design of interventions to prevent disease and promote adaptive aging.

Use our increased understanding of the underlying science to maximize the positive effect of physical activity on older adults. Several studies strongly suggest that modest physical activity may have beneficial effects in maintaining health — including mental health — and that these benefits are possible even at advanced ages.

For example, weight-bearing exercise can build bone strength, protecting against osteoporosis and subsequent fragility fractures, and balance exercises such as Tai Ji Quan may help prevent future falls. We will:. Continue to foster research into the molecular, cellular, and physiological mechanisms by which physical activity improves health.

Support further research on the effects of physical activity programs on older adults within specific age groups and develop strategies for promoting adherence. Support basic and translational research on the behavioral, psychological, and interpersonal mechanisms that support initiation and long-term engagement in physical activity over the adult lifespan.

Continue to support and conduct research to understand hormone changes in older adults and pursue the development of interventions to address these changes without unwanted side effects.

Counteracting some effects of aging by supplementing hormones such as estrogen, testosterone, human growth hormone, melatonin, and DHEA dehydroepiandrosterone is an area of active study, but there are concerns that individuals may be taking such agents before their safety and efficacy have been established.

NIA will support studies to understand the biological action of hormonal changes in older men and women, assess whether or not hormone therapy will improve health, investigate the use of compounds to produce the beneficial responses of hormones in the body without detrimental side effects, and determine the potential to regulate hormone production in specific body tissues where increased or decreased amounts of these hormones are favorable to health.

Support and conduct research to understand and address the needs of people with multiple chronic health conditions. Data from the Centers for Disease Control and Prevention show that more than half of Americans ages 65 and older are living with two or more chronic conditions.

NIA will support research to identify, test, and disseminate interventions to facilitate optimal management of multiple conditions.

Improve the safe use of medications by older adults. Managing medications can be complex for older adults; their medications are often prescribed by more than one physician, for multiple health problems.

Complications include adverse drug interactions and interactions with dietary supplements coupled with the physiological and functional changes associated with aging or age-related diseases.

Research supported and conducted by NIA will improve our understanding and maximize the effectiveness of medications, develop new technical aids for physicians to monitor drug use, and provide new technologies and information to enable patients to manage medications better and avoid adverse reactions.

Develop strategies to reduce falls and their consequences. Research supported and conducted by NIA will continue to identify safety risks for older adults in home and work environments, improve screening strategies, and develop and disseminate information important to reducing the risk of falls.

Explore new ways to improve safety in the home and community through studies of ergonomics and the built environment. This will include continuing research to identify cost-effective alterations in design that can reduce injuries and provide a safer environment for older adults, and an environment that encourages physical activity and social engagement.

Pursue a better understanding of needs and develop interventions to improve the safety of older drivers. NIA will continue to support research to identify factors such as visual impairment, hearing, attention, speed of processing, and other cognitive changes that put older drivers at risk of automobile accidents.

In addition, we will continue to support the development of tools for assessing visual, cognitive, and other abilities associated with safe driving, interventions to improve the physical and cognitive skills necessary for safe driving, and technology and design changes to accommodate or compensate for the special needs of older drivers.

We will also support research to understand the dynamics of making the decision to stop driving, the implications of that decision for the health and well-being of older adults, and alternative transportation options that help older adults maintain as much independence as possible.

This research will provide the insights needed to develop guidelines for older adults, their health care providers, and family members. NIA will help develop and evaluate improved biochemical, imaging, and other techniques and tools to measure the well-being of older adults as well as symptoms of disease and disability.

As new interventions are ready, the institute will disseminate information about the interventions to the public and health care communities, working to help move interventions into mainstream medical practice.

Investigate the mechanisms by which lifestyle interventions affect aging-related changes and determine how individuals can maintain function with age or regain that function after loss due to immobility, illness, or trauma.

After peaking in early adulthood, most tissue functions decline with advancing age. This leads to increased risk of developing diseases such as cardiovascular disease and cancer and may lead to declines in overall health and quality of life.

Further research is needed on the mechanisms through which common interventions, both medical and behavioral, may slow physical and cognitive decline. NIA will continue to support research into the mechanisms of functional decline and its delay, with the goals of identifying molecular targets for drug interventions and treatments that minimize losses and promote the recovery of function after illness or trauma.

Support the development of behavioral interventions based on principles of basic behavioral and social science and designed with an eye to real-world implementation, in line with the NIH Stage Model.

Because behavioral interventions frequently do not move beyond efficacy testing to effectiveness or implementation, NIH has developed a model to define and clarify the activities in behavioral intervention development and to facilitate scientific development of interventions that are both potent and implementable.

NIA will use this model as a guide for developing interventions that will be effective in real-world settings. Learn more about the NIH Stage Model.

Identify, characterize, and where appropriate, develop interventions for physiological changes that influence the risk of age-related diseases across the human lifespan. Studies will include changes that are associated with increased risk of disease and disabling conditions such as sarcopenia reduced muscle mass , as well as those that are associated with exceptional health and longevity.

Conduct clinical studies and encourage the translation of new interventions to the clinical setting. As mechanisms, pathways, and processes of disease are better defined, and as potential healthspan-extending interventions are validated in model systems,development and testing of clinical applications in humans can begin.

We will pursue the use of novel, flexible research designs where appropriate, and we will work with others to facilitate the navigation of barriers to the translation of promising compounds into clinical trials and ultimately approval by the U.

Food and Drug Administration. Support comparative effectiveness research. NIA will continue to support research to identify the relative merits of differing interventions for older adults. For example, investigators are testing the effectiveness of different interventions in improving quality and efficiency, eliminating disparities in treatment, and reducing unwarranted variations in expenditures at hospitals.

Families and others who care for people with chronic disease frequently face emotional stress as well as physical and financial burdens. At present, the direct economic costs of caregiving to caregivers and society are unknown, and it is not well understood how caregiving impacts the health and well-being of some caregivers and why some caregivers thrive in the experience of caregiving, whereas others experience distress, burden, and unhealthy outcomes of their own.

Using approaches grounded in basic behavioral and social science, investigators will continue to develop and evaluate strategies to improve social support, skills training, and assistive services both for those who cope with chronic disease and for their caregivers. These initiatives should result in more effective and implementable approaches for prevention, treatment, and rehabilitation, as well as the ultimate adoption of these approaches in real-world contexts.

Research supported and conducted by NIA will clarify needs and patterns of family caregiving and how people make decisions on providing care and inform guidance on support and skills, including a focus on families with diverse ethnic and socioeconomic backgrounds.

Develop strategies to help older adults and their families prepare for and manage age-associated changes in health, income, function, and roles.

Thank you for visiting Pharmaceutical-grade ingredient compliance. Prevetion are using a prevejtion version ailmentx limited Pharmaceutical-grade ingredient compliance for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Aging is a gradual and irreversible pathophysiological process. The following zilments was printed in the Guardian's Zilments and clarifications column, Monday 8 June prevengion The article below got Age-rlated Pharmaceutical-grade ingredient compliance backwards Age-related ailments prevention calculating where you Pharmaceutical-grade ingredient compliance Appetite control techniques book the body mass index. We should have said: multiply your height by itself in metres. Take your weight in kilogramsand divide it by the height figure you worked out. Anything between 18 and 25 is deemed a healthy outcome. What's the best way to protect ourselves from ill health as we get older?