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INTRODUCTION

It also increases healthspan in most studies and is protective in many age-related disease models. Other drugs, including metformin and acarbose, also extend mouse lifespan Harrison et al. Continued efforts should be directed at identifying and optimizing new molecules with these properties, and understanding those already identified Kennedy and Pennypacker, Ultimately, drug combinations may be optimal.

Further, many aging drugs approved for a single chronic disease e. Therefore, a thorough analysis of drugs clinically approved for chronic diseases should be performed to identify those with the potential to increase healthspan. Conserved longevity pathways have been identified across disparate eukaryotic species. However, aging also depends on environmental factors, which may be modifiable. Yet, the specific environmental influences on aging, aside from obvious culprits such as smoking and obesity, remain poorly understood. Moreover, stochasticity plays a major role in aging processes.

There is enormous variability in longevity traits among genetically identical individuals across all species tested. The causes of this stochasticity and its role in aging and age-related diseases remain poorly understood. Numerous aging genes have been identified in non-vertebrates, which now should be used to develop a systems level understanding of aging including both genetic and environmental influences.

Studies should incorporate multiple assessments of cellular and organismal function, including transcriptomics, proteomics and metabolomics, as well as readouts of macromolecular damage and activation of stress response pathways. Achieving a holistic view of aging in organisms such as yeast, worms and flies will likely impact our understanding of vertebrate aging, as did the identification of single genes in those organisms.

It is also critical in mammals to assess the relationship among genetics, environment and drug interventions to predict responses in human healthspan trials. Human genome association studies have identified aging-associated gene variations from either genome-wide unbiased or gene targeted studies, examining orthologs of animal aging genes Deelen et al.

Working between mouse and human genetics will accelerate identification of human aging genes and their mechanisms. Strategies should include generating orthologous or identical human mutant alleles in mice, modeling rare variants in genes from conserved longevity pathways. The lack of validated molecular biomarkers of human aging has impeded progress.

However, recent studies have uncovered promising candidates that if validated could be used to test interventions. Epigenetic studies are among the most exciting, with reports indicating that human age can be predicted by analyzing DNA methylation status. It remains unclear whether these markers forecast chronologic or biologic age, which are likely distinct. If they indeed measure biologic age, then a major hurdle to initiating human studies will be overcome. Also, if similar DNA methylation sites are identified in mice, they could be validated by determining whether interventions such as rapamycin delay the appearance of an aging profile and whether chronic stressors accelerate it.

Other avenues to molecular biomarkers, including metabolomic and proteomic approaches, are also yielding promising candidates and deserve equal attention. Increasingly, inflammation is being linked to aging and chronic disease Salvioli et al. Acute inflammatory responses to insults such as injury and infection are critical for organismal health and recovery. However, the basal inflammatory response rises with age, leading to low level chronic inflammation that is likely maladaptive, promoting aging.

Interventions designed to reduce chronic inflammation while maintaining an effective adaptive response may have broad benefits. Senescent cells accumulate in multiple tissues during aging, and have a unique senescence-associated secretory profile SASP that includes many pro-inflammatory cytokines Coppe et al. Cell senescence, whereby cells irreversibly cease proliferation in response to stress, was long suspected of driving organismal aging. However, the number of senescent cells in most aged tissues is limited.

The SASP potentially explains how a few senescent cells can have broad, adverse effects by secreting pro-inflammatory factors with autocrine, paracrine and endocrine activities.

The epidemic of chronic disease and understanding epigenetics

It is important to understand the in vivo consequences of senescent cells, and identify interventional strategies that may mitigate their effects. Recent genetic strategies to ablate senescent cells in mice set the stage for determining to what extent they drive aspects of normal aging Baker et al. Metabolic dysregulation accompanies aging and is exacerbated by chronic diseases such as type II diabetes. Among the critical questions to be addressed is how overnutrition and obesity affect the aging metabolome, whether pro-longevity interventions suppress age-related metabolic dysfunction, and how these interventions act in individuals with type II diabetes.


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These issues are relevant to inflammation as well, since adipose tissue is a major source of inflammatory cytokines. Determining how the pro-inflammatory response in adipose tissue is initiated and propagated, and the systemic effects of this response on aging should be a high priority. Links between altered metabolism and inflammation may be underlie connections between aging pathways previously thought independent.

While yeast, worms, flies and mice have been powerhouse aging models, there are fundamental gaps in the knowledge they provide. Understanding the diversity of biological processes that can accelerate or protect against age-related decline is critical, and is best achieved by investment in new model organisms that accentuate other aspects of aging. A major limitation in aging research is the lack of primate and other vertebrate models for preclinical testing. Primates, often rhesus monkeys, are intermediate between rodents and clinical trials in humans. However, rhesus monkeys live decades, making aging studies long and expensive.

One solution is to develop a second primate model — the marmoset, whose lifespan is much shorter. Other short-lived vertebrates such as the African killifish, may be useful for the same reason — aging and disease studies can be performed more rapidly than current counterparts like zebrafish and mice. While human genetic data on aging and age-related diseases is exploding, the speed of hypothesis testing in current vertebrate models is lagging and a short-lived vertebrate may provide a solution.

Another model to consider is dogs, which live in their owner's environment, are well understood with regard to aging and disease, and comprise a wide range of pedigrees, providing genetic diversity. Finding strategies to extend healthspan in dogs may be an excellent prelude to achieving the same goals in humans. Exceptionally long-lived species also offer promise. While several species such as clams are intriguing, the naked mole rat has recently garnered interest.

These rodents are approximately the same size as mice, but reach 30 years and are apparently devoid of cancer. Comparative studies and genome sequencing have suggested possible mechanisms that underlie their extreme longevity. One particularly informative research path may be to engineer naked mole rat longevity mechanisms into mice. The goal of slowing aging has fascinated humankind for millennia, but only recently acquired credibility.

Recent findings that aging can be delayed in mammals raise the possibility of prolonging human healthspan. The exact mechanism of a specific condition or treatment on AP-1 activation and the relative role of different MAPKs in these processes are diverse. Upon activation, AP-1 binds to the O -tetradecanoylphorbolacetate response element and induces transcription of a variety of genes involved in multiple cellular functions, such as proliferation, survival, differentiation, and transformation.

It interacts and binds to the transmembrane receptor Frizzled. Because NFAT is associated with the regulation of various genes, including cytokines, cell cycle, differentiation, and apoptosis, the noncanonical pathway can modulate cell behavior via gene transcription. HIFs are transcription factors that function in response to the available oxygen in the cellular environment — specifically, in low-oxygen conditions hypoxia.

On activation, this complex affects the transcription of numerous hypoxia-inducible genes. However, in hypoxic conditions HIF prolyl-hydroxylase is inhibited because it utilizes oxygen as a cosubstrate Semenza, In stabilized hypoxic conditions, HIF-1 upregulates several genes such as glycolysis enzyme, vascular endothelial growth factor, plasminogen activator inhibitor 1, angiopoietins 1 and 2, platelet-derived growth factor B, the TIE-2 receptor, and matrix metalloproteinases.


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HIF-1 is a potent inducer of metastatic genes including chemokine receptor 4, its ligands [SDF-1], and lysyl oxidase in a broad range of tumor cells Arya et al. NRF2 plays a major role as a central regulator of the adaptive response to oxidative stress. NRF2-induced activation of genes is inhibited by small Maf proteins, including MafG and MafK, to maintain the oxidation level of the intracellular environment. PPARs are nuclear receptor proteins, which function as transcription factors that regulate the expression of genes Michalik et al.

PPARs play essential roles in the regulation of cellular differentiation, development, metabolism, and tumorigenesis in higher organisms Belfiore et al.

Introduction

There are three forms of PPAR: Because saturated fatty acids have been shown to induce the expression of inflammatory gene products in several cell types Shi et al. The Roman physician Cornelius Celsus was the first to characterize inflammation, and in the 19th century the German physician Rudolf Virchow suggested a link between inflammation and chronic disease.

The major chronic diseases associated with inflammation and aging are cancer, CVD, diabetes, pulmonary disease, and neurological disease Figure 2. It is evident from extensive observations and experiments within the last few decades that most chronic diseases are preceded by a chronic low level of inflammation. Molecular studies on the causes of inflammation have shown that numerous biomarkers are involved in the process of inflammation. Aging results in an increase of inflammatory cytokines that contribute to the progression of many degenerative diseases McGeer and McGeer, ; van't Veer et al.


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As people grow and age, inflammation starts due to several environmental and physiological factors. Chronic inflammation damages cells of the brain, heart, arterial walls, and other body structures, leading to various inflammatory diseases such as heart disease, Alzheimer disease, Parkinson, disease rheumatoid arthritis, psoriasis, and prostatitis. As a person ages the levels of the inflammatory markers are often sharply elevated, indicating the presence of an underlying inflammatory chronic disorder Bremmer et al. Chronic inflammation has also been linked to the biological aging process Ferrucci et al.

Sarcopenia, or muscle loss with aging, is driven by a smoldering inflammatory state induced by elevated IL-6 and CRP levels Jensen, Cancer is one of the major diseases caused by chronic inflammation. Various proinflammatory biomarkers have been found to be elevated in several cancer types. That the overproduction of cytokines in cancer patients is associated with cancer-related fatigue is well documented.

For instance, the overproduction of IL-6 in patients with multiple myeloma is associated with more severe disease Klein et al.

Age-Associated Chronic Diseases Require Age-Old Medicine: Role of Chronic Inflammation

Similarly, breast cancer patients had elevated cytokines level Schmidt et al. The elevation of cytokines makes the diseases more severe. CVD is also associated with aging: Of these markers, only high-sensitivity CRP is well standardized and widely available. The levels of CRP and IL-6 have been shown to be significantly higher among persons who subsequently developed diabetes than among those who did not Pradhan et al.

Multiple sclerosis is an age-related autoimmune disease that affects the brain and spinal cord. This disease is characterized by damage to the myelin sheath, the protective covering that surrounds nerve cells, causing the nerve impulses to slow down or not function at all. For most patients the neurologic deterioration progresses over time. It usually affects people beginning in their 20s or 30s and is one of the most common causes of nontraumatic disability among young and middle-aged people.

This disease can be triggered by chronic inflammation of the central nervous system.

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In patients with multiple sclerosis, the levels of COX-2—derived prostaglandins are elevated in the cerebrospinal fluid Palumbo et al. This disease can begin at the ages of 15—30 years, and by the time a person reaches 60—80 years of age it becomes severe. Symptoms manifest not only in the intestine but also in other organs such as eyes and joints. Chronic diseases are the leading causes of death and disability in the United States: However, most of these diseases are preventable by adopting lifestyle changes such as eating nutritious foods, being physically active, and avoiding tobacco.

Because most chronic diseases have been linked to diet, modifying a diet could prevent or delay them. Relatively low intake of fruit and vegetables is a risk factor for many of the most important chronic diseases Block et al. Natural products such as fruits, vegetables, spices, legumes and cereals A and their bioactive components B linked to beneficial health effects against age associated chronic diseases.

A growing body of research is showing that fruits and vegetables are critical to good health. Fruits and vegetables contain essential vitamins, minerals, fiber, and phytochemicals that protect from chronic disease.

Aging: a common driver of chronic diseases and a target for novel interventions

More than 25, phytochemicals have been identified that may have potential against various cancers. These phytochemicals are safe and usually target multiple cell signaling pathways Aggarwal and Shishodia, Major chemopreventive compounds identified from fruits and vegetables include carotenoids, vitamins, resveratrol, quercetin, silymarin, sulphoraphane, and indolecarbinol Figure 3A. Fruits and vegetables in whole or their active components have been shown to act against several chronic diseases. For instance, in a study of primary breast cancer cases with control cases in Germany, intake of vegetables and whole-grain products was inversely associated with the risk of breast cancer Adzersen et al.

In another study, lycopene, which is present in fruits such as watermelon, apricots, pink guava, grapefruit, rose hip, and tomatoes, demonstrated anticancer activity in both in vitro and in vivo tumor models as well as in humans Nishino et al. Ursolic acid is found in several fruits, including rosemary, apple, beefsteak, pear, plum, bearberry, loquat, and jamun Liu, It exhibits anticancer potential against breast cancer Es-saady et al.

Ursolic acid targets a wide spectrum of signaling pathways, such as cell cycle progression, cell proliferation, and cell survival. It has also been shown to inhibit spontaneous or chemical-induced tumorigenesis in mammary glands, liver, lung, cervix, and gastrointestinal tract in different animal model studies Aggarwal and Ichikawa, Other than these several other fruits and vegetable act as anticancer agents.

Fruits and vegetables also have shown to reduce mortality by CVD. Evidence indicates that persons who consume more fruits and vegetables often have a lower prevalence of important risk factors for CVD, including hypertension, obesity, and type 2 diabetic mellitus. In a study of elderly Massachusetts residents, the risk of death was lower among those who consumed large amounts of carotene-containing fruits and vegetables than among the residents who ate small amounts Gaziano et al.

Greater intake of fruit and cruciferous vegetables may be inversely associated with the risk of rheumatoid arthritis. Rheumatoid arthritis appears to be less severe in southern Mediterranean countries, such as Italy and Greece, where fruit, vegetables, and olive oil are consumed in greater amounts than in many other countries Pattison et al. Further, a recent experimental study demonstrated that fruits and vegetables suppress the production of the inflammatory agents involved in arthritis Siddique and Saleem, Fruit and vegetable intake has also been associated with the decrease of multiple sclerosis Ghadirian et al.

In addition, experimental studies have shown that fruits and vegetables also suppress the inflammatory risk factors involved in chronic diseases other than arthritis. Without a doubt, the consumption of fruits and vegetables reduces the age-associated progression of chronic diseases. Spices are used all over the world to add flavor, taste, and nutritional value to food. It has been demonstrated that phytochemicals Figure 3B such as curcumin which is found in turmeric , diallyldisulfide garlic , thymoquinone black cumin , capsaicin red chili , gingerol ginger , anethole licorice , diosgenin fenugreek , and eugenol clove, cinnamon possess therapeutic and preventive potential against several chronic diseases.

Besides these phytochemicals, ellagic acid clove , ferulic acid fennel, mustard, sesame , apigenin coriander, parsley , betulinic acid rosemary , kaempferol clove, fenugreek , sesamin sesame , piperine pepper , limonene rosemary , and gambogic acid kokum have potential to act against chronic diseases. Extensive research over the past several years has indicated that spices and their bioactive components might be used for preventive care and in treating different types of cancer by modulating the different stages of tumorigenesis, including tumor cell survival, proliferation, invasion, and angiogenesis.

The anticancer activities of spices are mediated through the suppression of inflammation. Several other spices and spice-derived nutraceuticals have shown anti-inflammatory and antitumor activities. Animal studies have also shown the benefits of spices. In one study, oral administration of extracts of spices such as black pepper, asafoetida, pippali, and garlic increased the life span of mice transplanted with Ehrlich ascites tumor by In another study, the addition of Garam masala a mixture of food-seasoning spices suppressed dimethylbenz[a]anthracene DMBA -induced translactational and transplacental carcinogenesis in mice.

Garlic, ginger, cloves, mustard, bay leaf, caper, oregano, thyme, and other spices are protective against CVD. Spices are effective and powerful preventative agents because they modify risk factors associated with CVD, including raised cholesterol and triglyceride levels, high blood pressure, sticky platelets, and chronic systemic inflammation. The compounds found in spices also help to control many of the pathological conditions that underlie diabetes and metabolic syndrome. Spices have been shown to block the inflammation believed to drive diabetes Aggarwal, , and they lower blood sugar level, improve cholesterol and lipid status, and reduce blood pressure.

In both animal experiments and clinical trials, spices such as fenugreek seed, garlic, onion, and turmeric have been documented to possess antidiabetic potential Srinivasan, Spices can also be used in the prevention and treatment of multiple sclerosis Kannappan et al. The effects of spices against chronic diseases are mediated through the suppression of age-associated inflammatory markers Surh, Consumption of whole-grain cereal and legumes forms the basis of a healthy diet.

Growing evidence suggests that cereals and legumes play important roles in the etiology of chronic diseases. The major cereals or whole-grain foods are wheat, rice, and maize; others include barley, sorghum, millet, rye, and oats. The most commonly consumed legumes are beans, lentils, lupins, peas, and peanuts. These cereals and legumes contain chemopreventive antioxidants and anti-inflammatory phytochemicals such as vitamins and polyphenols Figure 3B. Cereals and legumes have been found to reduce the risk of several chronic diseases, including cancer.

The consumption of whole-grain cereals and legumes lowers the risk of cancers of the oral cavity, pharynx, esophagus, gallbladder, larynx, bowel, colorectum, prostate, breasts, liver, ovaries, bladder, renal, and thyroid gland as well as lymphomas, leukemias, and myeloma Chatenoud et al. In a multicenter case-control study of African-American, white, Japanese, and Chinese men with prostate cancer, intake of legumes was inversely related to prostate cancer Kolonel et al.

Mechanistic studies have shown that fibers and phytochemicals present in whole-grain cereals and legumes have chemopreventive action against a wide variety of cancers. For example, isoflavones including daidzein, genistein, and equol are nonsteroidal diphenolic compounds that are found in leguminous plants and have antiproliferative activities. Tocotrienol and inositol hexaphosphate, which are abundantly present in various high-fiber foods such as cereals and legumes, have exhibited anticancer activity in both in vitro and animal models.

These compounds interfere with key pathways in malignancy by inhibiting cell proliferation, cell cycle progression, metastasis, invasion, and angiogenesis and by inducing apoptosis Kolappaswamy et al. Consumption of wholegrain cereal and legumes can protect against CVD. A hypocaloric diet that included oats improved systolic blood pressure and the lipid profile compared with a hypocaloric diet without oats Saltzman et al.

The isoflavones present in legumes, such as in soy protein, have also been shown to reduce CVD risk factors. In an experimental study with monkeys, isoflavones or phytoestrogen-intact soy protein had favorable effects on plasma lipid and lipoprotein concentrations, specifically by significantly reducing low-density and very-low-density cholesterol concentrations, in both males and females Anthony et al. The isoflavone genistein has been shown to act against the risk of CVD.

Urinary incontinence or bladder problems , dizziness, a tendency to fall, and vision and hearing problems are other geriatric syndromes. Geriatric syndromes usually have more than one cause, and involve several different body systems. In addition, one geriatric syndrome often contributes to another. Urinary incontinence, for example, may lead to a bladder infection, which may, in turn, cause delirium.

Age-Associated Chronic Diseases Require Age-Old Medicine: Role of Chronic Inflammation

Like chronic diseases, geriatric syndromes can limit older adults' abilities to function, and result in their needing a lot of healthcare services. The study included more than 11, adults who were 65 or older. The researchers checked to see how many of the adults had at least one of five conditions.