Department of Cardiovascular Biology and Medicine Niigata University Graduate
School of Medical and Dental Sciences

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The incidence of lifestyle-related diseases such as diabetes, arteriosclerosis, and hypertension increases with advancing age, resulting in the development of ischemic heart disease and cerebral stroke. It has been suggested that chronic inflammation evoked in various tissues associated with aging is a cause of the development and progress of lifestyle-related diseases. However, the mechanism was unknown. These diseases can be recognized as characteristics of aging because the underlying conditions including chronic inflammation are observed commonly in many aged persons. In other words, the ultimate research target for developing the next-generation therapy for lifestyle-related diseases is supposed to be the mechanism itself for regulating human aging and lifespan. Researches on the basis how individual clinical status changes with aging have been performed until now; however, no comprehensive research from the viewpoint of aging and longevity has been conducted. Normally, human normal somatic cells go into an irreversible growth arrest called cellular senescence after a certain time of division. It has been also reported that the lifespan correlates with the age of the donor of the cultivated cell and the lifespan of the cell obtained from patients with premature aging syndrome is significantly shorter.

Therefore, we started the research on aging based on the hypothesis that “aging at the cellular level contributes to a part of characteristics of individual aging, especially, pathologic characteristics.”

Vascular aging

Aging cells in vascular tissue

It has not been clear whether the vascular cell senescence engages in vascular aging and atherosclerosis. We reported for the first time that senescent vascular cells were observed in the human atherosclerotic plaque using a method called senescence-associated (SA)β-gal assay (Figure) (Circulation 2002). These senescent vascular cells exhibited characteristics of age-associated vascular dysfunction such as elevated expression of pro-inflammatory cytokines. Therefore, vascular cell senescence was supposed to be a new mechanism underlying the pathophysiology of atherosclerosis. Telomere hypothesis is an important hypothesis for the mechanism of cellular senescence. Telomeres get shortened with cell division inducing p53-dependent cellular senescence. On the other hand, telomerase is an enzyme that adds telomeres onto chromosome ends. We have disclosed the molecular mechanisms for regulating the activity of telomerase in vascular cells (Circ Res 2001). We have also demonstrated that introduction of telomerase could suppress the cellular senescence and improve the chronic inflammation of aged vessels (Mol Cell Biol 2001), on the contrary, if dysfunction of telomere is introduced, vascular cells immediately undergo senescence resulting in vascular dysfunction including elevation of chronic inflammation (Circulation 2002) .

Furthermore, we have reported that telomere-independent p53-dependent cellular aging signals through the angiotensin II/ Ras/ERK axis, the insulin/Akt axis, and the oxidative stress signal pathway also cause chronic inflammation resulting in the development of atherosclerosis, which could be improved by suppressing the cellular aging signals (Circulation 2003, Circulation 2006, EMBO J 2004, Circ Res2008).

It is suggested that circadian rhythm is impaired by aging and disturbed circadian rhythm accelerates aging. We also suggested that the vascular cell senescence gets involved in non-dipper type hypertension observed in aged individuals by disturbing the expression of clock genes that control the circadian rhythm (Circ Res 2006, Circ Res 2008) .

We have shown that the clinical state of heart failure is worsened through senescence of vessels and bone marrow. Expression of p53 was increased in cardiac endothelial cells and bone marrow cells in response to pressure overload, leading to up-regulation of intercellular adhesion molecule-1 (ICAM1) expression by endothelial cells and integrin expression by bone marrow cells. Deletion of p53 from endothelial cells or bone marrow cells significantly reduced ICAM1 or integrin expression, respectively, as well as decreasing cardiac inflammation and ameliorating systolic dysfunction during pressure overload. Norepinephrine markedly increased p53 expression in endothelial cells and macrophages. Reducing adrenergic receptor expression in endothelial cells or bone marrow cells attenuated cardiac inflammation and improved systolic dysfunction during pressure overload. These results suggest that activation of the sympathetic nervous system promotes cardiac inflammation by up-regulating ICAM1 and integrin expression via p53 signaling to exacerbate cardiac dysfunction. Inhibition of p53-induced inflammation may be a novel therapeutic strategy for heart failure. (J Mol Cell Cardiol 2015).

Diabetes and aging

Aging of fat causes insulin resistance

Aging is known to increase the prevalence of metabolic disorders like diabetes. Therefore, we hypothesized that cellular aging might influence insulin resistance and accelerate the development of diabetes. By using various genetic models including telomerase-deficient mice, we have shown that p53 in adipose tissue is critically involved in insulin resistance, which underlies age-related cardiovascular and metabolic disorders (Nat Med 2009). Telomerase-deficient mice with short telomeres developed insulin resistance when fed a high-calorie diet. The adipose tissue of these mice showed senescence-like changes, such as increases in activity of senescence-associated β-galactosidase, expression levels of p53, and production of pro-inflammatory cytokines. Resection of senescent adipose tissue improved insulin resistance in telomerase-deficient mice, whereas implantation of senescent adipose tissue into wild-type mice led to impairment of insulin sensitivity and glucose tolerance in the recipients. Up-regulation of p53 induced expression of pro-inflammatory cytokines and accumulation of macrophages in adipose tissue. We also found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of type 2 diabetic mice and promoted senescence-like changes, thereby increasing production of pro-inflammatory cytokines. Inhibition of p53 activity significantly ameliorated these senescence-like changes of adipose tissue, decreased the expression of pro-inflammatory cytokines, and improved insulin resistance in type 2 diabetic mice. Conversely, up-regulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from diabetic patients also showed senescence-like features. These data indicate that cellular aging signals (particularly p53 in adipose tissue) up-regulate the expression of pro-inflammatory molecules, thereby promoting the infiltration of macrophages into adipose tissue. This leads to a further increase in the production of pro-inflammatory cytokines by adipose tissue, which induces insulin resistance and glucose intolerance (Figure). Our results demonstrate a previously unappreciated role of adipose tissue p53 in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a novel target for the treatment of diabetes.

Semaphorine is a key factor to connect aging of fat and inflammation.

As shown above, chronic inflammation associated with fat senescence is related to the development and progress of diabetes. Then, we tried to identify a key molecule that connected fat senescence and inflammation. As a result, we found that Semaphorin 3E (Sema3E) was an indispensable molecule for adipose tissue inflammation associated with obesity and systemic insulin resistance (Cell Metab 2013). Expression of Sema3E and its receptor plexinD1 was up-regulated in the adipose tissue of a mouse model of dietary obesity. Inhibition of the Sema3E-plexinD1 axis markedly reduced adipose tissue inflammation and improved systemic insulin resistance in this model. Conversely, over-expression of Sema3E in adipose tissue provoked inflammation and systemic insulin resistance. Sema3E promoted infiltration of macrophages, and this effect was inhibited by disrupting plexinD1 expression in macrophages. Disruption of adipose tissue p53 expression led to down-regulation of Sema3E expression and improved adipose tissue inflammation in the dietary obesity model. These results indicate that Sema3E acts as a chemoattractant for macrophages, with p53-induced up-regulation of Sema3E expression provoking adipose tissue inflammation and systemic insulin resistance in association with dietary obesity (Figure).

Ingestion of high fat calorie food

Additionally, we have shown that vascular aging is closely related to diabetes (Cell Reports 2014)(Figure). Endothelial expression of p53 was markedly up-regulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that up-regulated the expression of peroxisome proliferator-activated receptor- coactivator-1 in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Inhibition of endothelial p53 also improved dietary impairment of glucose transport into skeletal muscle by up-regulating endothelial expression of glucose transporter 1. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. Conversely, up-regulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.

Cardiac aging

Continuous pressure load activates p53 and develops heart failure. Heart failure activates p53 of fat and accelerates insulin resistance.

It is known that the onset of heart failure is increased with age. It is also suggested that p53-dependent aging signals are enhanced in cardiomyocytes by telomere dysfunction and accumulated DNA damages with age. With regard to age-associated hypertension, cardiac hypertrophy is formed as an adaptive response to increased workload to maintain cardiac function. Prolonged cardiac hypertrophy causes heart failure; however, the mechanism is not clear and it was a great mystery in the cardiovascular field. We have demonstrated that cardiac angiogenesis is critically involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is crucial for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (HIF-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced accumulation of p53 that inhibited HIF-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation further developed hypertrophy and restored cardiac dysfunction under chronic pressure overload. These results suggest that anti-angiogenic property of p53 plays a critical role in the transition from cardiac hypertrophy to heart failure (Nature 2007, J Exp Med 2009, Circ Res2010, Circulation 2010) (Figure).

We have also demonstrated that that there is a vicious cycle where activation of p53-dependent aging signals in heart cause activation of p53 in fat via the sympathetic nervous system causing chronic inflammation and increasing production of proinflammatory cytokines, which results in insulin resistance and worsens heart failure, forming a vicious cycle (J Clin I nvest 2010, Cell Metab 2 012) (Figure). Inhibition of fat senescence could block the vicious cycle and improve cardiac dysfunction.

Development of new therapy by controlling signal of aging

Aging-related disease

As shown above, neural and humoral factors somehow regulate the signal network between organs contributing to chronic inflammation provoked by activation of p53-dependent aging signals of tissue, which plays an important role in the development of lifestyle-related disease associated with aging and excessive calorie intake. We observed that age-related activation of p53-dependent signals and its associated chronic inflammation were suppressed in long-lived mice. Therefore, it is expected that there is a molecular basis upstream and downstream of p53- dependent aging signals that is common to these long-lived mice. It is not desirable to make p53 a direct target from the viewpoint of acceleration of carcinogenesis. However, it is possible to control chronic inflammation in lifestyle-related diseases by searching the molecular basis upstream or downstream of excessive p53-dependent aging signal that causes chronic inflammation. This research group will clarify the molecular mechanisms of aging by using long-lived and premature aging animal models and develop the strategy of the new therapy for lifestyle- related disease.

It has become clear that the activation of p53 signal accompanying DNA damage is related to clinical state of various aging-related diseases such as diabetes, heart failure and atherosclerosis (Figure). The underlying mechanisms include reduction of tissue regeneration function, endocrine dysfunction and transformation of intracellular metabolism as well as chronic inflammation (Cell Metab 2014). It is expected that a therapy targeting at them will be developed in the future.

Related documents
  1. DNA Damage Response and Metabolic Disease (pdf : 1.3Mb)
  2. Role of Cellular Senescence in Lifestyle-Related Disease (pdf : 745kb)
  3. Vascular aging: insights from studies on cellular senescence, stem cell aging, and progeroid syndromes (pdf : 558kb)
  4. Vascular Cell Senescence: Contribution to Atherosclerosis (pdf : 281kb)
  5. Role of telomere in endothelial dysfunction in atherosclerosis (pdf : 210kb)
  6. BIBLIOGRAPHY (pdf : 121kb)