**1. Introduction**

The world population ages rapidly, mostly because of increasing longevity and declining fertility [1]. The average lifespan of the human populations is increasing worldwide and it is predicted that in 2035, nearly every fourth individual will be 65 years or older [2]. Aging

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

is a complex phenomenon with a large impact on society. Aging is recently an emerging topic since the life expectancy is rising and because aging itself is the basis for the development of age-related diseases such as cardiovascular disease (CVD), cancer, neurodegenerative diseases and degenerative metabolic diseases (e.g. *diabetes mellitus* type 2) [3]. Since age is the largest risk factor for CVD, the prevalence of these ailments increases dramatically with increasing age. Over 80% of all cases of coronary artery disease and more than 75% of those of congestive heart failure are observed in elderly patients [4]. In order to improve prevention and care for patients, it is important to analyze processes linked with cardiac aging. Prevalence of high blood pressure, obesity and metabolic syndrome correlate with age, and all these conditions facilitate the development of cardiomyopathies that are the major cause of chronic disability, morbidity and mortality in the elderly. Although the long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of CVD and neurodegeneration, intrinsic alterations in the heart and the vascular system occur during lifespan and render the cardiovascular system more vulnerable during senescence. The possible link between aging and senescence was first described in 1961 [5] and it based on the inability of telomeres to sustain their lengths. In addition to this, other events and signals were identified including non-telomeric/genotoxic stress generated by various signals, such as mitochondrial deterioration, oxidative stress, DNAreplication "stress" or activated oncogenes [6]. Several lines of evidence indicate mitochondrial dysfunction to be a major contributor to cardiovascular senescence. Damaged mitochondria are bioenergetically less efficient and they are producing excessive amounts of reactive oxygen species (ROS) with detrimental structural and functional consequences [7]. The ROS impair excitation-contraction coupling, cause arrhythmias, and contribute to cardiac remodeling by inducing cardiac hypertrophy, apoptosis, necrosis, and fibrosis [8]. However, antioxidant interventions in patients with CVD yielded only disappointing results so far [9].

with the challenge to dissect the communication and maintenance of the individual compartments. Part of this is to ensure proteostasis (folding, unfolding and degradation) to generate a homeostasis of the functional proteome and to clear mistargeted/damaged proteins. It is not easy, because every submitochondrial compartment needs to control its redox milieu, which is interestingly highly different, e.g. the inner membrane separates the reducing matrix from the more oxidizing intermembrane space [13]. The complexity of the proteome supersedes that of the genome due to alternative splicing events and post-translational modifications (PTMs). Specific position has the mitochondrial intermembrane space (MIMS) with its role in protein and lipid transport, regulation and assembly of the respiratory transport system, regulation of redox processes, coordination of apoptosis and metal ion homeostasis [14]. One of the big challenges of future research will be to investigate how the mitochondrion communicates with the cytosol and the nucleus. The MIMS exhibits specific redox environment and controlled porine-facilitated leakiness through the outer membrane allowing the free diffusion of small molecules (less than 5 kDa) that might harbor candidates mediating the communication from signaling pathways occurring inside the mitochondria toward other organelles [15].

Interplay Between Mitochondrial Proteins and Age-Associated Risk of Cardiovascular Diseases

http://dx.doi.org/10.5772/intechopen.71789

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Mitochondrial homeostasis is associated with overall cellular fitness and cellular longevity. Therefore, it determines also normal physiology of organ systems and performance of the body. Recent studies suggest that restoration of mitochondrial dynamics and mitophagy could delay organ senescence and prevent age-associated cardiac diseases. Here, we discuss the current understanding of mitochondria with particular focus on the heart, specifically the close relationship between mitochondrial dynamics or mitophagy suggesting a possible link

Cells undergo widespread changes and develop specific characteristics during senescence that are considered as senescence markers. However, no individual marker has been so far identified as entirely selective parameter for cellular senescence. Nevertheless, a combination of several markers might be evaluated and can help to define the current stage of senescence. Phenotypically, the increase in size and protein content was reported in senescent cells [16, 17] which is in agreement with our results. The data in **Table 1** show that the total protein concentration was elevated in senescent (27 months old) rat mitochondria by 40% (p < 0.01).

**6 14 27**

to the regulation of redox metabolism, and intercellular protein communication.

Homogenate 20.87 ± 2.50 23.96 ± 1.46 19.19 ± 2.96 Mitochondria 5.69 ± 0.61 5.38 ± 0.49 9.56 ± 0.05\*\*

**Table 1.** Protein concentration in homogenate and mitochondria during aging in heart (yet unpublished data).

Values are expressed as Mean ± SEM of 5 individual experiments, \*\*p<0.01; significantly different in comparison to 6

**2. Cellular senescence and mitochondria**

**Protein concentration (mg/ml) Age (months)**

months old rats.

The accumulation of abnormal/dysfunctional mitochondria is usually a consequence of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis [7]. Autophagic flux is generally decreased in aging hearts. Murine loss-of-function models for autophagy develop exacerbated cardiac dysfunction that is accompanied by accumulation of misfolded proteins and dysfunctional organelles. On the other hand, stimulation of autophagy in mouse models improves cardiac function and enables to study a protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby alleviating aging-associated pathology in the heart. Multiple lines of evidence suggest that autophagy is required for many mechanisms that mediate lifespan extension, such as caloric restriction. These results are pointing out the possibility that autophagy may play an important role in combating the adverse effects of aging in the heart [10]. At the molecular level, the aging process is associated with accumulation of damaged proteins and organelles, partially due to defects in protein quality control systems. Since most cellular functions are performed by proteins, aging may be, in part, the consequence of a deregulation or malfunction of the cellular proteome [11]. Modern techniques enabled the investigation of the internal structure and morphology of mitochondria and revealed a highly complex compartmentalization [12] with the challenge to dissect the communication and maintenance of the individual compartments. Part of this is to ensure proteostasis (folding, unfolding and degradation) to generate a homeostasis of the functional proteome and to clear mistargeted/damaged proteins. It is not easy, because every submitochondrial compartment needs to control its redox milieu, which is interestingly highly different, e.g. the inner membrane separates the reducing matrix from the more oxidizing intermembrane space [13]. The complexity of the proteome supersedes that of the genome due to alternative splicing events and post-translational modifications (PTMs). Specific position has the mitochondrial intermembrane space (MIMS) with its role in protein and lipid transport, regulation and assembly of the respiratory transport system, regulation of redox processes, coordination of apoptosis and metal ion homeostasis [14]. One of the big challenges of future research will be to investigate how the mitochondrion communicates with the cytosol and the nucleus. The MIMS exhibits specific redox environment and controlled porine-facilitated leakiness through the outer membrane allowing the free diffusion of small molecules (less than 5 kDa) that might harbor candidates mediating the communication from signaling pathways occurring inside the mitochondria toward other organelles [15].

Mitochondrial homeostasis is associated with overall cellular fitness and cellular longevity. Therefore, it determines also normal physiology of organ systems and performance of the body. Recent studies suggest that restoration of mitochondrial dynamics and mitophagy could delay organ senescence and prevent age-associated cardiac diseases. Here, we discuss the current understanding of mitochondria with particular focus on the heart, specifically the close relationship between mitochondrial dynamics or mitophagy suggesting a possible link to the regulation of redox metabolism, and intercellular protein communication.
