The amount of active bone Efects, where blood cells Antioxidant-Fortified Beverages produced, decreases. The genes of cells program a process that, when triggered, results in death of the cell. Maeo, Dr. Sports Med.

Resisting the effects of aging -

As people age, hearing high-pitched sounds becomes more difficult. This change is considered age-associated hearing loss presbycusis. For example, violin music may sound less bright. Articulating consonants clearly may be more helpful than speaking more loudly to older people who have trouble understanding speech.

The most frustrating consequence of presbycusis is that words become harder to understand. As a result, older people may think that other people are mumbling.

Even when other people speak more loudly, older people still have difficulty understanding the words. The reason is that most consonants such as k, t, s, p, and ch are high-pitched, and consonants are the sounds that help people identify words.

Because vowels are lower-pitched sounds, they are easier to hear. Understanding what women and children say may be more difficult than understanding what men say because most women and children have higher-pitched voices.

Gradually, hearing lower pitches also becomes more difficult. Many older people have more trouble hearing in loud places or in groups because of the background noise. See also Effects of Aging on the Mouth and Teeth Effects of Aging on the Mouth and Teeth With aging, taste sensation may diminish.

Older people may find their food tastes bland so, for more taste, they may add abundant seasonings particularly salt, which is harmful for some people read more and Effects of Aging on the Ears, Nose, and Throat Effects of Aging on the Ears, Nose, and Throat Aging affects the function of the ears, nose, and throat in varying degrees.

Generally, when people are in their 50s, the ability to taste and smell starts to gradually diminish. Both senses are needed to enjoy the full range of flavors in food. The tongue can identify only five basic tastes: sweet, sour, bitter, salt, and a taste called umami commonly described as meaty or savory.

The sense of smell is needed to distinguish more subtle and complex flavors such as raspberry. As people age, taste buds on the tongue decrease in sensitivity. This change affects tasting sweet and salt more than bitter and sour. The ability to smell diminishes because the lining of the nose becomes thinner and drier and the nerve endings in the nose deteriorate.

However, the change is slight, usually affecting only subtle smells. Because of these changes, many foods tend to taste bitter, and foods with subtle smells may taste bland. The mouth tends to feel dry more often, partly because less saliva is produced.

Dry mouth Dry Mouth Dry mouth is caused by a reduced or absent flow of saliva. This condition can cause discomfort, interfere with speech and swallowing, make wearing dentures difficult, cause bad breath halitosis read more further reduces the ability to taste food. As people age, the gums recede slightly.

Consequently, the lower parts of the teeth are exposed to food particles and bacteria. Also, tooth enamel tends to wear away. See also Overview of Tooth read more caries and thus make tooth loss more likely. See also Effects of Aging on the Skin Effects of Aging on the Skin Aging results in thinning of the dermis and epidermis.

The underlying fat layer can be lost as well. The decrease in volume and overall effectiveness of all three skin layers results in a number The skin tends to become thinner, less elastic, drier, and finely wrinkled.

However, exposure to sunlight over the years greatly contributes to wrinkling and to making the skin rough and blotchy. People who have avoided exposure to sunlight often look much younger than their age.

The skin changes partly because collagen a tough, fibrous tissue that makes skin strong and elastin which makes skin flexible become chemically changed and less flexible; also, the aging body produces less collagen and elastin.

As a result, the skin tears more easily. The fat layer under the skin thins. This layer acts as a cushion for the skin, helping protect and support it.

The fat layer also helps conserve body heat. When the layer thins, wrinkles are more likely to develop, and tolerance for cold decreases. The number of nerve endings in the skin decreases. As a result, people become less sensitive to pain, temperature, and pressure, and injuries may be more likely.

The number of sweat glands and blood vessels decreases, and blood flow in the deep layers of the skin decreases. As a result, the body is less able to move heat from inside the body through blood vessels to the surface of the body.

Less heat leaves the body, and the body cannot cool itself as well. Thus, the risk of heat-related disorders, such as heatstroke, is increased. Also, when blood flow is decreased, the skin tends to heal more slowly. The number of pigment-producing cells melanocytes decreases.

As a result, the skin has less protection against ultraviolet UV radiation, such as that from sunlight. Large, brown spots age spots develop on skin that has been exposed to sunlight, perhaps because the skin is less able to remove waste products.

The skin is less able to form vitamin D when it is exposed to sunlight. Thus, the risk of vitamin D deficiency Vitamin D Deficiency Vitamin D deficiency is most commonly caused by a lack of exposure to sunlight.

Some disorders can also cause the deficiency. The most common cause is lack of exposure to sunlight, usually when read more increases. See also Effects of Aging on the Nervous System Effects of Aging on the Nervous System Aging affects all parts of the nervous system: the brain, the spinal cord, and the peripheral nerves see also Changes in the Body with Aging: Brain and nervous system.

Brain function varies The number of nerve cells in the brain typically decreases. However, the brain can partly compensate for this loss in several ways:. Levels of the chemical substances involved in sending messages in the brain tend to decrease, but some increase.

Nerve cells may lose some of their receptors for these chemical messages. Blood flow to the brain decreases. Because of these age-related changes, the brain may function slightly less well.

Older people may react and do tasks somewhat more slowly, but given time, they do these things accurately. Some mental functions—such as vocabulary, short-term memory, the ability to learn new material, and the ability to recall words—may be subtly reduced after age After about age 60, the number of cells in the spinal cord begins to decrease.

Usually, this change does not affect strength or sensation. As people age, nerves may conduct signals more slowly. Usually, this change is so minimal that people do not notice it. Also, nerves may repair themselves more slowly and incompletely.

Therefore, in older people with damaged nerves, sensation and strength may be decreased. See also Effects of Aging on the Heart and Blood Vessels Effects of Aging on the Heart and Blood Vessels The heart undergoes changes with aging.

Many changes are due to the development of heart disorders, which become more common with aging. Other changes are due to aging itself. See also Biology The heart and blood vessels become stiffer. The heart fills with blood more slowly. The stiffer arteries are less able to expand when more blood is pumped through them.

Thus, blood pressure tends to increase. Despite these changes, a normal older heart functions well. Differences between young and old hearts become apparent only when the heart has to work hard and pump more blood—for example, during exercise or an illness.

An older heart cannot speed up as quickly or pump as fast or as much blood as a younger heart. Thus, older athletes are not able to perform as well as younger athletes. However, regular aerobic exercise can improve athletic performance in older people. See also Effects of Aging on the Respiratory System Effects of Aging on the Respiratory System The effects of aging on the respiratory system are similar to those that occur in other organs: maximum function gradually declines.

Age-related changes in the lungs include Decreases in peak The muscles used in breathing, the diaphragm and muscles between the ribs, tend to weaken. The number of air sacs alveoli and capillaries in the lungs decreases. Thus, slightly less oxygen is absorbed from air that is breathed in.

The lungs become less elastic. In people who do not smoke or have a lung disorder, these changes do not affect ordinary daily activities, but these changes may make exercising more difficult.

Breathing at high altitudes where there is less oxygen may also be harder. The lungs become less able to fight infection, partly because the cells that sweep debris containing microorganisms out of the airways are less able to do so.

Cough, which also helps clear the lungs, tends to be weaker. See also Effects of Aging on the Digestive System Effects of Aging on the Digestive System Because the digestive system has a lot of reserve built into it, aging has less effect on its function than it does on the function of other organ systems.

Nonetheless, aging is a factor in Overall, the digestive system is less affected by aging than most other parts of the body. The muscles of the esophagus contract less forcefully, but movement of food through the esophagus is not affected. Food is emptied from the stomach slightly more slowly, and the stomach cannot hold as much food because it is less elastic.

But in most people, these changes are too slight to be noticed. Certain changes cause problems in some people. The digestive tract may produce less lactase , an enzyme the body needs to digest milk.

As a result, older people are more likely to develop intolerance of dairy products lactose intolerance Lactose Intolerance Lactose intolerance is the inability to digest the sugar lactose because of a lack of the digestive enzyme lactase, leading to diarrhea and abdominal cramping.

Lactose intolerance is caused People with lactose intolerance may feel bloated or have gas or diarrhea Diarrhea in Adults Diarrhea is an increase in the volume, wateriness, or frequency of bowel movements.

See also Diarrhea in Children. The frequency of bowel movements alone is not the defining feature of diarrhea read more after they consume milk products. In the large intestine, materials move through a little more slowly. In some people, this slowing contributes to constipation Constipation in Adults Constipation is difficult or infrequent bowel movements, hard stool, or a feeling that the rectum is not totally empty after a bowel movement incomplete evacuation.

See also Constipation The liver tends to become smaller because the number of cells decreases. Less blood flows through it, and liver enzymes that help the body process drugs and other substances work less efficiently. As a result, the liver may be slightly less able to help remove drugs and other substances from the body.

And the effects of drugs—intended and unintended—last longer. See also Effects of Aging on the Urinary Tract Effects of Aging on the Urinary Tract As people age, a number of changes happen throughout the genitourinary tract.

As people age, there is a slow, steady decline in the weight of the kidneys. After about age 30 to 40, about two The kidneys tend to become smaller because the number of cells decreases. Less blood flows through the kidneys, and at about age 30, they begin to filter blood less well.

As years pass, they may remove waste products from the blood less well. They may excrete too much water and too little salt, making dehydration more likely.

The maximum volume of urine that the bladder can hold decreases. Thus, older people may need to urinate more often. The bladder muscles may contract unpredictably become overactive , regardless of whether people need to urinate.

The bladder muscles weaken. As a result, they cannot empty the bladder as well, and more urine is left in the bladder after urination. The muscle that controls the passage of urine out of the body urinary sphincter is less able to close tightly and prevent leakage.

Thus, older people have more difficulty postponing urination. These changes are one reason that urinary incontinence Urinary Incontinence in Adults Urinary incontinence is involuntary loss of urine.

read more uncontrollable loss of urine becomes more common as people age. In women, the urethra the tube through which urine leaves the body shortens, and its lining becomes thinner. The decrease in the estrogen level that occurs with menopause may contribute to this and other changes in the urinary tract.

In men, the prostate gland tends to enlarge. In many men, it enlarges enough to interfere with the passage of urine and to prevent the bladder from emptying completely. As a result, older men tend to urinate with less force, to take longer to start the stream of urine, to dribble urine at the end of the stream, and to urinate more often.

Older men are also more likely to be unable to urinate despite having a full bladder called urinary retention Urinary Retention Urinary retention is inability to urinate or incomplete emptying of the bladder.

People who have incomplete emptying of the bladder may have urinary frequency or urinary incontinence. If the This disorder requires immediate medical care. See also Effects of Aging on the Female Reproductive System Effects of Aging on the Female Reproductive System Around menopause, changes in the female reproductive organs occur rapidly.

Menopause is defined as 1 full year after the last menstrual period. Menstrual cycles stop, and the ovaries stop The effects of aging on sex hormone levels are more obvious in women than in men.

In women, most of these effects are related to menopause Menopause Menopause is the permanent end of menstrual periods, ovulation, and fertility.

For up to several years before and just after menopause, estrogen levels fluctuate widely, periods become irregular read more , when the levels of female hormones particularly estrogen decrease dramatically, menstrual periods end permanently, and pregnancy is no longer possible.

The decrease in female hormone levels causes the ovaries and uterus to shrink. The tissues of the vagina become thinner, drier, and less elastic a condition called atrophic vaginitis. In severe cases, these changes can lead to itching, bleeding, pain during intercourse, and a need to urinate immediately urinary urgency Urinary Urgency A compelling need to urinate urgency , which may feel like almost constant painful straining tenesmus , can be caused by bladder irritation.

Uncontrolled loss of urine incontinence may The breasts become less firm and more fibrous, and they tend to sag. These changes make finding lumps in the breasts more difficult. Some of the changes that begin at menopause such as lower hormone levels and vaginal dryness may interfere with sexual activity.

However, for most women, aging does not greatly detract from enjoyment of sexual activity. Not having to worry about becoming pregnant may enhance sexual activity and enjoyment. See also Effects of Aging on the Male Reproductive System Effects of Aging on the Male Reproductive System It is not clear whether aging itself or the disorders associated with aging cause the gradual changes that occur in men's sexual functioning.

The frequency, duration, and rigidity of erections In men, changes in sex hormone levels are less sudden. Levels of the male hormone testosterone decrease, resulting in fewer sperm and a decreased sex drive libido , but the decrease is gradual.

Although blood flow to the penis tends to decrease, most men can have erections and orgasms throughout life. However, erections may not last as long, may be slightly less rigid, or may require more stimulation to maintain. A second erection may require more time. Erectile dysfunction Erectile Dysfunction ED Erectile dysfunction ED is the inability to attain or sustain an erection satisfactory for sexual intercourse.

See also Overview of Sexual Dysfunction in Men. Every man occasionally has read more impotence becomes more common as men age and is often due to a disorder, usually a disorder that affects blood vessels such as a vascular disease or diabetes Diabetes Mellitus DM Diabetes mellitus is a disorder in which the body does not produce enough or respond normally to insulin, causing blood sugar glucose levels to be abnormally high.

Symptoms of diabetes may See also Effects of Aging on the Endocrine System Effects of Aging on the Endocrine System The endocrine system consists of a group of glands and organs that regulate and control various body functions by producing and secreting hormones.

Hormones are chemical substances that affect Aldosterone levels decrease, making dehydration more likely. This hormone signals the body to retain salt and therefore water. Insulin , which helps control the sugar glucose level in blood, is less effective, and less insulin may be produced.

Insulin enables sugar to move from the blood into cells, where it can be converted to energy. The changes in insulin mean that the sugar level increases more after a large meal and takes longer to return to normal. For most people, the changes in the endocrine system have no noticeable effect on overall health.

But in some, the changes may increase the risk of health problems. For example, the changes in insulin increase the risk of type 2 diabetes Diabetes Mellitus DM Diabetes mellitus is a disorder in which the body does not produce enough or respond normally to insulin, causing blood sugar glucose levels to be abnormally high.

Thus, exercise and diet, which can enhance insulin 's action, become more important as people age. The amount of active bone marrow, where blood cells are produced, decreases. Therefore, fewer blood cells are produced. Nonetheless, the bone marrow can usually produce enough blood cells throughout life.

Problems may occur when the need for blood cells is greatly increased—for example, when anemia Overview of Anemia Anemia is a condition in which the number of red blood cells is low.

Red blood cells contain hemoglobin, a protein that enables them to carry oxygen from the lungs and deliver it to all parts read more or an infection develops or bleeding occurs. Genetic interference with proper signal transduction by various approaches shares as outcome an extension of lifespan This pituitary hormone promotes IGF-1 production from the liver and other tissues, but the two hormones have partly opposite effects.

For instance, growth hormone induces insulin resistance but promotes insulin production whereas IGF-1 promotes insulin sensitivity and reduces insulin secretion Therefore, outcomes of genetic disturbance of the regulatory balance between growth hormone, IGF-1 and insulin are difficult to interpret.

A body-wide knockout of the insulin receptor leads to early postnatal lethality whereas mice heterozygous for mutant and wildtype receptors did not show an altered lifespan despite some functional impairment of insulin signaling In another study, mice heterozygous for a knockout of the insulin receptor showed no differences in lifespan to wildtype littermates in females but an increase in maximum lifespan in males Many studies have observed an extended lifespan in mice if growth hormone expression, or binding to its receptor are impaired.

Longevity is increased in both sexes of Ames or other dwarf mice with deficient production of growth hormone together with prolactin and thyroid stimulating hormone or with isolated growth hormone deficiency 29 , Mice with disruption of the growth hormone receptor gene express a similar phenotype The longevity mechanism of mice with deficient growth hormone activity has not been fully elucidated, but it is of interest that there is a strong association with enhanced insulin sensitivity Similar analyses of IGF-1 are hampered by the fact that lack of functional IGF-1 receptors severely impairs development.

Therefore, mice heterozygous for a receptor gene knockout were analyzed. Prolongation of lifespan was modest and seen in female mice only 33 — IGF-1 receptor function can also be affected by deletion of insulin receptor substrate genes. This approach also impairs insulin signaling.

Mice lacking insulin receptor substrate 1 exhibit increased longevity For the insulin receptor substrate 2 gene, deletion in all tissues of mice was not found to increase lifespan while deletion in brain tissue only promoted longevity 38 Table 1.

The opposing effects of growth hormone and IGF-1 on insulin sensitivity and production leads to the question whether insulin action itself is more closely related to longevity than the two other anabolic hormones. In mice, modulation of circulating insulin levels and insulin sensitivity often but not always were reported to affect the lifespan which supports a role of insulin actions in the aging process.

In one study, mice with reduced insulin sensitivity because of impaired insulin receptor function exhibited an increased lifespan in males but not in females. Increased insulin sensitivity because of deficiency of protein tyrosine phosphatase 1B or overexpressed peroxisome proliferator activated receptor gamma coactivator-1α was associated with a shortened lifespan Another strain of mice with impaired insulin receptor function also exhibited insulin resistance and hyperinsulinemia, but without an impact on lifespan The significance of the association was carried by alleles of nine genes, AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2 , and YWHAG This study did not observe the well documented association of FOXO3A with longevity, possibly because nonagenarians rather than centenarians were analyzed.

Another additional factor determining the outcome of insulin actions on longevity might be the overall metabolic rate. A high metabolic rate is associated with increased production of reactive oxygen species ROS.

For instance, small-breed domestic dogs exhibit a higher mass-specific metabolic and growth rate than large dogs, and therefore oxidative damage of lipids is seen. Nevertheless, small-breed dogs live significantly longer 46 , In mice, heavier body weight is associated with increased epigenetic aging and earlier death 48 , Similar findings have been reported for humans.

In Southern Chinese adults, the basal metabolic rate was inversely correlated with all-cause mortality in males, but not in females Within a local population, people of smaller size have a higher life expectancy, in different regions of the world It may be concluded that within a species a higher growth rate is associated with shorter lifespan, but this is not explained by a higher metabolic rate.

In humans, epidemiological studies suggest a pro-aging effect of insulin. The higher longevity in shorter men is also associated with lower fasting insulin concentrations In adults with normal glucose tolerance, there is a parallel increase of fasting insulin levels and insulin resistance with aging, and this is associated with central obesity 56 , Hyperinsulinemia and insulin resistance are important risk factors for type 2 diabetes as well as hypertension and cardiovascular disease 58 — Another approach of studying the health impact of hyperinsulinemia is to determine the insulinemic potential of the diet as assessed by food frequency questionnaires evaluated by measuring circulating C-peptide concentrations.

Of note, these associations were independent of BMI. Insulin is a potent anabolic hormone. A Mendelian randomization analysis found that genetic variants which code for a higher insulin response to glucose challenge are strongly associated with increased BMI which is considered as proof of a causal relationship between increased insulin secretion and body weight gain This fits with the observation that insulin therapy favors weight gain Conversely, pharmacological lowering of circulating insulin concentrations in obese people by diazoxide caused greater weight loss than diet alone Treatment of obese persons with the somatostatin analogue octreotide led to weight loss in conjunction with a decrease of insulin levels 68 , Lifestyle changes or other interventions known to improve risk factors of age-associated disease and cardiovascular mortality cause lower insulin levels, as reported for calorie-restricted diets, intermittent fasting or bariatric surgery 70 — Vegetarian diets are also associated with lower insulin resistance and lower fasting insulin levels, even in comparison with matched lean controls, and appear to improve healthspan and possibly also lifespan 74 , Another lifestyle parameter associated with better healthspan is physical exercise, which causes lower fasting and post-challenge insulin levels as well as improved insulin sensitivity 76 — Although insulin is an essential hormone for growth and maintenance of complex organisms 79 , the above findings suggest that elevated insulin levels promote age-associated diseases.

One cellular response to permanently elevated insulin levels is partial downregulation of insulin signaling via the insulin receptor, causing the phenomenon of insulin resistance.

A higher amount of alternatively spliced type A insulin receptor lacking exon 11 also may contribute to insulin resistance by directing insulin signaling towards the mitogen activated kinase pathway which promotes cell proliferation and tumor development Signaling via the PI3K-AKT pathway is not only affected by modulation of insulin receptor function but also enzyme activities downstream.

The diversity of proteins involved in the PI3K-AKT signaling pathway allows for varying outcomes of signaling, and this complexity is only partially resolved. The resulting decreased arterial smooth muscle relaxation is aggravated by the non-suppressed insulin-dependent influx of calcium ions which enhances vascular contractility, resulting in upregulated vascular tone which increases the risk of vascular events 89 , Other hormonal actions that are less or not affected by insulin resistance and may even be upregulated with the concomitant hyperinsulinemia include upregulation of PI3K-AKT dependent lipogenesis in hepatocytes and of the mechanistic target of rapamycin complex 1 mTORC1 activity, the latter resulting in increased protein synthesis and impaired autophagy 91 — Increased systemic insulin levels and concomitant insulin resistance during the progression to type 2 diabetes is associated with chronic overactivation of the mTORC1 signaling pathway and cell stress in the context of a high protein synthesis rate During insulin resistance states and concomitant hyperinsulinemia there is, varying between tissues, phosphorylation of several Forkhead Box O FOXO transcription factors and their retention in the cytoplasm.

resulting in suppression of muscle autophagy and protein degradation, among other effects 86 , 97 — The impact of elevated insulin levels on protein synthesis and autophagy is accompanied by the accumulation of proteins with multiple posttranslational modifications because of insufficient degradation which leads to endoplasmic reticulum stress 95 , Insulin signaling via phosphorylation of the Src homology 2 domain-containing transforming proteins SHC and subsequent activation of the mitogen-activated kinase protein kinase kinase MEK - extracellular signal-regulated kinase ERK is not affected by insulin resistance and contributes to these effects of hyperinsulinemia Figure 2 , Figure 2 Elevated insulin levels and insulin resistance favor age-associated diseases in humans.

Modest increases of insulin concentrations suffice to suppress lipolysis and support lipogenesis, promoting obesity. Hyperinsulinemia combined with insulin resistance cause activation of mTORC1 which in the context of less FOXO activation favors cell stress because of increased protein synthesis, eventually causing cell senescence.

Insulin resistance impairs endothelial NO synthase eNOS activity, limiting vascular relaxation. These findings suggest that increased insulin signaling because of elevated ambient levels causes cell stress, and there is a potentiating effect of insulin resistance.

The promotion of hepatocyte senescence by hyperinsulinemia is absent in mice with a liver-specific knockout of the insulin receptor whereas enhanced senescence was still occurring in white adipose tissue. In obese persons undergoing bariatric surgery, insulin levels were closely associated with markers of senescence in liver tissue Increased levels of insulin were also observed to promote senescence of human adipocytes in vitro as well as in vivo High ambient insulin concentrations also drive mouse neurons into a senescence-like state, in vitro and in vivo Another age-associated marker is DNA damage.

Prolonged incubation of animal or human cells with 0. Whether insulin resistance or the concomitant hyperinsulinemia promotes enhances telomere attrition in peripheral blood leukocytes in addition to cell stress has not been studied in detail.

Cross-sectional studies suggest that that insulin resistance is associated with increased telomere shortening in some groups but not in others — A positive association was also noted in the follow-up of cohorts — with one exception These observational studies also found an association between telomere attrition and other parameters such as adiposity, hypertension or circulating sirtuin-1 concentrations.

Therefore, the association between telomere length and insulin levels may also be indirect. As reviewed above, high insulin concentrations cause cell stress because of excess anabolic activity which include i , increased lipogenesis and fat storage also in non-adipocytes, ii , increased protein synthesis and accumulation of non-functional polypeptides because of limited turnover capacity, iii , impaired autophagy activity, iv increased progression of stressed cells towards a senescent stage.

These changes are associated with mitochondrial dysfunction and increased levels of radical oxygen species , Hyperinsulinemia usually is accompanied by insulin resistance, but there is only partial suppression of insulin signaling, favoring lipogenesis as well as mTORC1 activation for protein synthesis and autophagy inhibition.

The relevance of enhanced mTORC1 activation for the aging process has been demonstrated by treating mice with the mTORC1 inhibitor rapamycin which resulted in less proliferative and protein synthesis activity concomitant with improved autophagy and increased longevity. These changes resemble effects of dietary restriction.

However, pharmacological inhibition of mTOR may reach a degree where detrimental consequences to the physiological balance are noted such as impaired immune cell activation, insulin resistance and beta islet cell damage 95 , , Insulin resistance in the presence of hyperinsulinemia helps maintain glucose homeostasis and decreasing metabolic and oxidative stress by depressing excess glucose influx , However, the concomitant suppression of NO production from endothelial NO synthase favors a pro-oxidant and inflammatory vascular milieu as well as vasoconstriction potentially favoring vascular damage Figure 2 87 — Taken together, hyperinsulinemia in the context of insulin resistance appears to exhibit a pro-aging role.

One well documented health risk associated with increased insulin levels is type 2 diabetes. We suggest here that this adaptive hormetic response also controls the pro-aging effect of insulin. The stress signals involved in inducing a hormetic response include oxygen radicals, misfolded proteins and decreased levels of ATP Figure 3.

Figure 3 Adaptive response to anabolic cell stress. These signals initiate an adaptive response to increase cellular resistance and restore proper physiological functions, including activation and nuclear transfer of Nrf2, an unfolded protein response and stimulation of AMP-activated protein kinases.

ROS, radical oxygen species; UPR, unfolded protein response; AMPK, AMP-activated protein kinases, inflamm. Oxygen radicals initiate a cell protective response by activation of nuclear factor erythroid 2 — related factor 2 Nrf2 , a key transcriptional factor for the expression of more than genes involved in cytoprotective processes such as redox regulation, xenobiotic metabolism, DNA repair, and protein homeostasis including the unfolded protein response — There is impairment of pro-inflammatory gene expression, including the suppression of nuclear factor kappa B NFkB and pro-inflammatory cytokines , Another effect of Nrf2 activation is the support of endothelial NO synthase expression and NO production Thus, activation of Nrf2 is an appropriate adaptive cellular response to the oxidative, inflammatory and vascular stress caused by hyperinsulinemia and concomitant insulin resistance, with an impact on aging Loss of proteostasis because of excessive protein synthesis is a major consequence of an acute rise of insulin levels, but this is apparently contained by the unfolded protein response of the endoplasmic reticulum Misfolded proteins signal the loss of proteostasis by binding to chaperone sensors which initiates a transcriptional program leading to a general increase of mechanisms involved in protein synthesis and turnover, the unfolded protein response This protective cell response is impaired in the presence of experimentally induced or diabetes-associated insulin resistance Low chaperone activity causes cell senescence A third important signal of cell stress is a decrease of ATP levels versus adenosine diphosphate ADP and adenosine monophosphate AMP concentrations, which results from increased consumption and deficient production of ATP.

Low ATP levels lead to the activation of AMP-activated protein kinases. This group of kinases modulates the activity of many metabolic enzymes, histones and transcription factors by phosphorylation and by promoting their acetylation.

One important consequence is the restoration of mitochondrial homeostasis — As mentioned, several lifestyle factors have been observed to lower levels of fasting and postprandial insulin as well as of insulin resistance.

These factors include dietary restriction and exercise 72 , Interestingly, dietary restriction or exercise cause an initial increase of oxidative or electrophile stress.

The resulting activation of the Nrf2 system appears to mediate much of the health effects observed — Many dietary phytochemicals such as polyphenols also cause the activation of Nrf2, in part with an involvement of the hydrocarbon receptor , , Another pathway of improving insulin resistance and concomitant hyperinsulinemia by lifestyle changes involves the gut, possibly by modulation of gut microbiota composition and activity may decrease gut leakage.

The resulting lower levels of bacterial compounds in circulation is associated with decreased production of pro-inflammatory immune mediators and increased insulin sensitivity Insulin resistance is a potentiating factor because of increased signaling via the mitogen-activated kinase pathway and less production of NO by endothelial NO synthase.

These potentially aging-promoting effects are contained by an adaptive cellular activity characterized by anti-oxidative, anti-inflammatory, protein chaperone, DNA repair and overall turnover process which is more potent in the long-lived human species than in short-lived models of aging research — Therefore, the pro-aging impact of insulin is less controlled in short-lived animal models such as nematodes and fruit flies.

Controlling factors are, on the one side, levels of insulin and insulin resistance, and, on the other side, the quality of cellular resistance to anabolic stress. This fits with the observation that centenarians exhibit low circulating insulin concentrations as well as high insulin sensitivity.

Of note, lifestyle factors that are considered to improve healthspan and possibly lifespan in humans modify both sides of the balance. Dietary restriction and exercise have been found to lower levels of insulin and insulin resistance.

Concomitantly, dietary restriction, dietary phytochemicals and exercise activate the Nrf2-dependent cellular stress response and modify microbiota composition and function in a favorable way. During aging, the cell stress response via Nrf2 becomes less potent but possibly not in centenarians — , and there is an age-dependent increase of circulating insulin and insulin resistance 52 , Both processes are supporting the pro-aging effects of insulin, and both may be targeted by dietary restriction and exercise.

HK: Writing — original draft. The work was supported by Gesellschaft von Freunden und Förderern der Heinrich-Heine-Universität Düsseldorf e. We thank Fraser W. Scott, the Ottawa Hospital Research Institute and University of Ottawa, Canada, for reviewing the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Insulin resistance, a reduction Resisting the effects of aging the agign of glucose disposal elicited by a Resisting the effects of aging insulin or, is Resistjng in Resistiing who are obese, and those with diabetes mellitus, and may develop with aging. Methods which Organic herbal supplements utilised to agijg insulin sensitivity include the hyperinsulinaemic-euglycaemic eftects hyperglycaemic oxidative stress and disease and Resistinng intravenous glucose tolerance tests. Several hormones and regulatory factors affect insulin action and may contribute to the insulin resistance observed in obesity. In addition, abnormal free fatty acid metabolism plays an important role in insulin resistance and the abnormal carbohydrate metabolism seen in individuals who are obese or diabetic. Thus, the mechanisms underlying the development of insulin resistance are multifactorial, and also involve alterations of the insulin signalling pathway. Aging is associated with an increase in bodyweight and fat mass. Not only is abdominal fat associated with hyperinsulinaemia but visceral adiposity is correlated with insulin resistance as well.

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