1.2. Aging and its Molecular Mechanisms

Ageing is one of the most complex biological phenomena found in nature and refers to the intrinsic, inevitable and irreversible process of loss of viability and increased vulnerability related to age (Comfort, 1964), leading to an increase in the mortality rate soon after death. maturity (FLATT, 2012), as illustrated in Figure 1.1.

Figura 1.1. Taxa de Mortalidade (lei de Gompertz–Makeham). Taxas de mortalidade, expressas em número de mortes a cada 100.000 pessoas, em função da idade da população norte-americana de 2002. A linha preta representa a função de Gompertz extrapolada das taxas de mortalidade após a maturidade. Retirado de CDC/NCHS, National Vital Statistics System, Mortality Data.

When we compare the increase in maximum life expectancy with the average expectation since the beginning of the last century (Figure 1.2), we find that the increase was minimal. This may be a sign that the interventions developed so far have not directly attacked the biology of ageing. However, this does not necessarily imply the inexistence of manipulable biological mechanisms of ageing. On the contrary, there is a growing volume of experimental evidence, obtained from a wide variety of organisms, suggesting the existence of at least nine molecular markers that characterize aging and are evolutionarily conserved, known as hallmarks of aging (LÓPEZ-OTÍN et al., 2013), shown in Figure 1.3.

Figura 1.2. Aumento da Expectativa de Vida no Último Século. Gráfico de barras representando a expectativa de vida máxima e média nos anos 1900 e 2000 (vermelho).

Figura 1.3. Os Marcadores do Envelhecimento. A figura ilustra os nove marcadores do envelhecimento: instabilidade genômica, desgaste telomérico, alterações epigenéticas, perda de proteostase, desregulação da detecção de nutrientes, disfunção mitocondrial, senescência celular, exaustão de célula tronco, e alteração da comunicação intracelular. Retirada de (LÓPEZ-OTÍN et al., 2013).

Aging markers are phenomena that manifest themselves naturally during aging and when experimentally aggravated, accelerate or delay the aging process (LÓPEZ-OTÍN et al., 2013). Such markers can be divided into three categories: primary, antagonistic and integrative.

‌ The main characteristics of primary markers are that they always have negative effects, such as DNA damage, chromosomal aneuploidy, mitochondrial DNA mutations, telomere shortening, epigenetic drift and imbalances in protein homeostasis (proteostasis). Antagonist markers have opposite effects depending on their intensity and can be seen as mechanisms developed to protect the body from damage or nutrient shortages. When at a low level, they can mediate beneficial effects, but when their activities are exacerbated or chronic, they can subvert their purpose and generate even more damage. An example of this would be senescence, which protects the body from the development of cancer, but when in excess, it can trigger aging (GORGOULIS; HALAZONETIS, 2010). A similar effect also occurs with reactive oxygen species (ROS, from English ‘Reactive Oxygen Species), which participate in the control of cell survival and signalling but can produce cell damage when at exacerbated levels (HARMAN, 1965). The third category constitutes the integrative markers. These directly affect homeostasis and tissue function and are represented by stem cell exhaustion and changes in intracellular communication.

‌ A hierarchy between the types of markers was proposed (Figure 1.4): the primary markers, whose harmful consequences accumulate progressively over time, can be considered as the first triggers of the aging process. Antagonistic markers, which in principle are beneficial and protective, become progressively deleterious in a process that is partially accelerated by primary markers. Finally, integrative markers arise when the damage accumulated by the other two markers can no longer be compensated for by tissue homeostatic regulation mechanisms (LOPEZ-OTÍN et al., 2013).

Figura 1.4. Interconexões funcionais entre os marcadores chaves do envelhecimento. Os nove marcadores moleculares do envelhecimento estão agrupados em 3 categorias: causas primárias de dano celular, respostas compensatórias e antagônicas ao dano, e aqueles que são os resultados dos dois outros grupos e responsáveis pelo declínio funcional associado ao envelhecimento. Retirada de (LÓPEZ-OTÍN et al., 2013).