A synopsis on aging-Theories, mechanisms and future prospects

Abstract

Answering the question as to why we age is tantamount to answering the question of what is life itself. There are countless theories as to why and how we age, but, until recently, the very definition of aging - senescence - was still uncertain. Here, we summarize the main views of the different models of senescence, with a special emphasis on the biochemical processes that accompany aging. Though inherently complex, aging is characterized by numerous changes that take place at different levels of the biological hierarchy. We therefore explore some of the most relevant changes that take place during aging and, finally, we overview the current status of emergent aging therapies and what the future holds for this field of research. From this multi-dimensional approach, it becomes clear that an integrative approach that couples aging research with systems biology, capable of providing novel insights into how and why we age, is necessary.

Keywords: Aging; Anti-aging therapies; Biochemistry; Biology; Senescence.

Fig. 1

Categorization of the main theories of aging. Classification based on the worked developed by (Semsei, 2000) and (de Magalhães, 2013).

Fig. 2

General mechanism of oxidative damage to biomolecules. Oxidative damage to lipids yields lipid peroxidation products, mainly localized at the cellular membrane, which results in a loss of membrane properties/function. Their reactive end products can induce damage to other molecules, such as proteins and DNA. In nuclear and mitochondrial DNA, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) is one of the predominant forms of free radical-induced oxidative lesions (Valavanidis et al., 2009). Potential outcomes include dysfunction of the affected biomolecules and interference with signaling pathways. Adapted from (Thanan et al., 2014).

Fig. 3

The cumulative effect of ROS over time. ROS accumulation, oxidative stress and the imbalance of the normal redox state increases exponentially with age, accompanied by a marked decline of the cell repair machinery. Note that, despite only depicting the general stress response pathways, a typical Golgi pathway has yet to be described. Nonetheless, multiple stress factors may influence gene expression in the nucleus and cell homeostasis via alterations in the function of the Golgi apparatus (Kourtis and Tavernarakis, 2011). The figure was partly created using Servier medical art image bank (Servier, France).

Fig. 4

The formation of AGEs and their mechanism of action at a cellular level. The positive feedback loop of NF-κB activation with subsequent RAGE expression is highlighted.

Fig. 5

Model of telomere shortening on aging.

Fig. 6

An integrated physiological view of the functional and structural changes observed during aging. Multiple feedback loops exist at both the genomic and the organ levels, suggesting that aging is an accelerated process, countered only by the robustness of each level. Adapted from (Kriete et al., 2006).

Fig. 7

Pathways of non-enzymatic degradation, repair, and replacement of aged proteins. Functional proteins can be covalently altered by a number of pathways (blue arrows). Enzymatic mechanisms exist that are capable of directly repairing, at least partially, this damage (red arrows), though, so far, no repair mechanisms have been described for many other types of damage. Altered proteins can be proteolytically digested to free amino acids and these can be used for synthesizing new functional proteins (green arrow). Adapted from (Clarke, 2003).

Fig. 8

Pathways of non-enzymatic chemical degradation of aspartyl and asparaginyl residues in proteins and of the methyltransferase-mediated repair mechanism. Spontaneous degradation of normal l-aspartyl and l-asparaginyl residues lead to the formation of a ring succinimidyl intermediate. This can spontaneously hydrolyze to either the l-aspartyl residue or the abnormal l-isoaspartyl residue. The l-isoaspartyl residue is specifically recognized by the protein l-isoaspartate (d-aspartate) O-methyltransferase. The result is the formation of an unstable methyl ester that is converted back to l-succinimidyl. Net repair occurs when the l-succinimidyl residue is hydrolyzed to the l-aspartyl form. With the exception of the repair methyltransferase step, all the reactions are non-enzymatic. Adapted from (Clarke, 2003).

Fig. 9

Confidence view of the predicted and know protein and chemical interactions. Stronger associations are represented by thicker lines. Protein-protein interactions are shown in blue, chemical-protein interactions in green and interactions between chemicals in red. ZFR – zinc finger RNA binding protein. FCGR3B – Fc fragment of IgG, low affinity IIIb, receptor (CD16b). ARL6IP6 – ADP-ribosylation-like factor 6 interacting protein 6. EML4 – echinoderm microtubule associated protein like 4. S100A8 – S100 calcium binding protein A8. C4B – complement component 4B. Predicted functional partners include catalase, SOD2 – superoxide dismutase 2; SOD3 – superoxide dismutase 3; NOS3 – nitric oxide synthase 3; GPX1 – glutathione peroxidase 1; AKT1 – v-akt murine thymoma viral oncogene homolog 1; GPX2 – glutathione peroxidase 2; NOX4 – NADPH oxidase 4; NOX5 – NADPH oxidase, EF-hand calcium binding domain 5; TYRP1 – tyrosinase-related protein 1. A more comprehensive and in-depth study of all the modified proteins during aging may yield strong known and/or predicted protein and chemical interactions. Data obtained using STITCH (Kuhn et al., 2014).

Fig. 10

Main metabolic pathways involved in the regulation of mammalian longevity and affected by CR. These include reduced cytokine levels, adiposity, thyroid hormone levels, IIS signaling and increased adiponectin. CR engages multiple downstream cellular pathways, including SIRT1 activation, insulin/IGF-1/phosphatidylinositol 3-kinase (PI3 K)/Akt signaling, as well as AMPK/mTOR and extracellular signal-regulated kinase 1/2 (Erk1/2) signaling. Ultimately, the collective response is believed to lead to the promotion of longevity through activation of stress defense mechanisms, autophagy and survival pathways, with concomitant attenuation of pro-inflammation mediators and cell growth. Pharmacologic approaches, such as those involving the use of rapamycin, metformin or resveratrol are believed to exert an analogous effect via the mechanisms shown. Arrows indicate the directional stimulatory effect and blunt-ended line an inhibitory one. IL-6 stands for interleukin-6, TNFα for tumor necrosis factor-α, NF-κB for nuclear factor-κB, IRS-1 for insulin receptor substrate-1 and PAI-1 for plasminogen activator inhibitor 1. Adapted from (Barzilai et al., 2012).