2.6. Altered Intercellular Communication

Cell-to-cell communication is essential for maintaining tissue homeostasis, and alterations in intercellular communication have been implicated in aging and age-related diseases.[37] For example, age-related changes in the extracellular matrix can lead to altered signaling through integrins and other cell surface receptors,[38] while changes in the secretion of growth factors and cytokines can disrupt paracrine signaling.[39] Altered intercellular communication can be detected by measuring the expression of cell surface receptors, secreted factors, or downstream signaling effectors.(ROS).[26] The observed decline in ATP production with age (8% per decade) causes energetic deficiency and likely contributes to lower physical performance in elders.[26] Elevated intracellular levels of ROS together with an imbalance in antioxidant defenses provoke oxidative stress known to be involved in the development of many pathological conditions.[27] Recent studies have suggested a more complex relationship between oxidative stress and aging, as some low levels of ROS may provoke signaling pathways associated with longevity[26,28]; moreover, most strategies to mitigate ROS have not led to lifespan extension in animal models.[28,29] Oxidative stress can be measured directly by ROS or indirectly by specific chemical derivatives resulting from ROS-induced modification of biological macromolecules (nucleic acids, proteins, carbohydrates, and lipids), which are typically more stable than ROS molecules and presented in detectable quantities in biological fluids and tissues. The predominant products of oxidative damage of nucleic acids are 8-oxo-2-deoxyguanosine (8-oxodG), 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), associated with many age-related conditions, including arthritis, osteoporosis, atherosclerosis, hypertension, cataracts, diabetes, and neurodegenerative diseases.[30] A reliable marker of lipid peroxidation is 8-iso prostaglandin F2 (F2-isoprostane), which is a peroxidation product of arachidonic acid or other polyunsaturated fatty acids presented in phospholipid membranes.[31] Similar to DNA damage markers, F2-isoprostane concentration increases with age and high levels are observed in a number of diseases commonly encountered in elderly patients.[30] The most abundant markers of protein oxidative modification are protein carbonyls. Proteins, lipids, or nucleic acids possessing free amino groups can non-enzymatically react with reducing sugars, and via a chain of intermediate reactions form cross-linked and non-degradable aggregates, termed advanced glycation end products (AGEs). Among the most representative and intensively studied AGEs are carboxymethyl-lysine, carboxymethyl-valine, and pentosidine.[32] AGEs accumulate slowly in human tissues during normal aging but may accelerate when blood glucose levels are elevated, suggesting that AGEs contribute to the pathophysiology of diabetic complications.[33,34] Some AGEs exhibit fluorescence, providing opportunities for the noninvasive detection of AGEs deposition in human tissues.[32] Advanced lipoxidation end-products (ALEs) formed by a non-enzymatic reaction between macromolecules and reactive aldehydic compounds, arising from lipid peroxidation, may also be used as an indicator of oxidative stress.[35] Proteostasis network machinery, mitochondrial dysfunction, and oxidative stress lead to loss of normal cell function and altered proliferation. As a result, cells can undergo a transition into an irreversible non-proliferative senescence state which contributes to decreased stemness. Besides a senescence state, cells can go into a reversible non-proliferative quiescent state or die by various cell death mechanisms. Altered paracrine and endocrine communication, as well as intercellular matrix remodeling, also affect cell functioning. Figure 1 provides an overview of molecular and cellular biomarkers of aging. Accumulation of molecular damage within a cell due to genomic instability and mutations, epigenetic modification, loss of proteostasis, mitochondrial dysfunction, and oxidative stress lead to loss of normal cell function and altered proliferation.of a single hematopoietic stem cell, suggesting that stem cell clones can persist for many decades in humans.[56]