Molecular Mechanisms of Aging Lecture Notes PDF

ADVANCED THERAPEUTIC TECHNOLOGIES LECTURE 4: 29/10/2024 MOLECULAR MECHANISMS OF AGING In 1956, it was proposed the free radical theory of aging, arguing that degenerative changes during aging are mediated by the harmful effects of free r...

ADVANCED THERAPEUTIC TECHNOLOGIES LECTURE 4: 29/10/2024 MOLECULAR MECHANISMS OF AGING In 1956, it was proposed the free radical theory of aging, arguing that degenerative changes during aging are mediated by the harmful effects of free radicals generated during normal cellular metabolism. Aging and degenerative diseases associated with it are attributed basically to the deleterious side attacks of free radicals on cell constituents and on the connective tissues. The free radicals probably arise largely through reactions involving molecular oxygen catalyzed in the cell by oxidative enzymes and in the connective tissues by traces of metals such as iron, cobalt and manganese. Another milestone in aging theory was reached in 1961. Indeed, in the continuous culture of human diploid cells, the lifespan of fibroblasts was first found to be limited. In the timeline there’s the representation of aging research and aging related diseases. For example, caloric restriction was showed to increase the lifespan of mice. Heterochronic parabiosis is a method used to facilitate a shared blood supply between two conjoined animals. One study indicated that approximately 50 cell types are susceptible to the accelerated aging effects of parabiosis and are susceptible to induced rejuvenation. In the experiment, two mice are putted together at different age (in heterochronic parabiosis), sharing the blood circulation. It was used to investigate cells’ origin and aging process. The older mouse affects the younger one and vice versa, so the oldest gets younger and vice versa thanks to their shared components. The lifespan resulted extended in the older mouse and reduced in the youngest mouse due to permanent epigenetic and transcriptome remodeling. The parabiosis reduced the epigenetic age of blood and liver based on several clock models. Parabiosis is better than blood exchange considering several experimental parameters. →Several theories have been proposed to explain the control of aging and its nature, to answer the question “Is aging programmed?”. In contrast to the programmed nature of development, it is still a matter of debate whether aging is an adaptive and regulated process or a consequence arising from stochastic accumulation of harmful events that culminate in a global state of reduced fitness, risk for diseases and death. Aging is not and cannot be programmed, but it reflects the continuation of an embryonic program into adulthood, which cannot be powered off but loses purpose with time. 1 Successful aging is a multidimensional concept, among which there are biomedical aspects (cognitive, physical functions, health), which are subjective and psychosocial factors (psychologically well adaptation) that are instead objective. What can affect aging is loneliness for sure, which has been defined as the perceived sense of isolation and among the most vulnerable ones, as elderly and those living with disabilities, rates of loneliness are very high. At a cellular level, aging hallmarks cause altered intracellular communication, stem cell exhaustion and cellular senescence; at molecular level there’s genomic instability, telomere shortening, epigenetic alteration, loss of proteostasis, compromised autophagy, mitochondrial disfunction; at a systematic level, we have nutritional dysregulation due to a reduced nutrient sensing. Genomic instability is a wide spectrum of alterations that include accumulation of nuclear DNA damage, alteration in mitochondrial DNA and nuclear architecture, and the formation of endogenous cytoplasmatic DNA and junk DNA. Regarding nuclear DNA damage accumulation, endogenous DNA damage is a major marker of genomic instability, especially DNA double strand breaks. DNA damage activates the DNA damage response and cell cycle checkpoints pathways, such as p53-p21 and p16INK4a-pRb pathways. Thus, cell cycle is blocked, preventing the transmission of the damaged genetic information to offspring cells. The number of genomic mutations has been positively associated with aging in all organs and analysis of centenarians have shown that long lived individuals have fewer somatic mutations and germ cell mutations than the general population, suggesting that they have more efficient DNA repair mechanisms to maintain genomic stability. Regarding mitochondrial DNA alterations, mtDNA is different from nuclear DNA because it contains only exons and lacks histone protection and an effective gene repair system. These features make it more susceptible to mutations. Moreover, mitochondria have a higher oxidative stress so mtDNA can be damaged and released from them, into the cytoplasm or out of cells (in extracellular fluids and cerebrospinal fluids). Circulating cell-free mtDNA is a novel signal for mitochondrial communication between distal tissues and has been associated with neurological disorders and systemic inflammations. As we age, mitochondrial DNA (mtDNA) becomes unstable, leading to damage. This instability triggers inflammation, a kind of immune response that becomes chronic with age. The damaged mitochondria then send distress signals, affecting communication between different parts of the cell (mitonuclear communication), between cells and organs, and even through hormones. These changes can activate stress responses like UPR (Unfolded Protein Response), alter metabolites, and release mitokines (mitochondrial signals). Altogether, these disruptions lead to a metabolic shift, where the body's energy production and usage become less efficient, contributing to aging symptoms and decreased physical function. Mitochondrial-derived peptides (MDPs) are produced in the mitochondria from short open reading frames (sORFs) found in mtDNA. These MDPs can act within the mitochondria or travel outside the cell to different tissues, like the brain and muscles, to signal and regulate various functions. Additionally, some MDPs can interact with the nucleus of the cell, influencing gene expression by activating transcription factors. These peptides play a role in cellular communication and may help protect against stress or damage, potentially influencing aging and metabolism. Among mitochondrial proteins we have humanin whose low levels are associated with worse cognition and age in animal models and humans and it attenuates pathology in Alzheimer’s disease animal models; MOTS-c whose low levels are associated with worse metabolic factors in humans; SHLP2 which acts as a protein chaperone. Modifies mitochondrial energetics and its low levels are associated with age in mice and prostate cancer in humans. 2 Endogenous cellular DNA is a contributing factor to aseptic inflammation, which occurs in the absence of pathogenic infection. It increases in cytoplasmic DNA levels in the CD4+ T cells of elderly human and mice and stimulates the proliferation and the activation of CD4+ T cells, thereby enhancing aging associated autoimmunity. Inflammation, indeed, is one of the main actors in age related diseases. Telomeres are formed by telomeric DNA and binding proteins. Telomeric DNA shortens with increasing number of cell division and telomere length is controlled by telomerase activity (high in human embryonic tissues and decreases progressively with age). Epigenetic alterations are one important aging hallmark. DNA methylation changes with age in a process termed epigenetic drift. The correlation between methylation and age is the epigenetic clock, that measures our biological age and predicts our lifespan. Moreover, histone modifications like acetylation, methylation, phosphorylation, ubiquitination and glycosylation change with aging. Furthermore, chromatin remodeling occurs with less efficiency and numerical abnormalities accumulate (leading to aneuploidy). Cellular senescence is one of the main mechanisms of aging. Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of stable permanent cell cycle arrest that is termed cellular senescence. Cellular senescence was originally defined as a stable exit from cell cycle caused by the finite proliferative capacity of cultured human fibroblasts. Then, senescence was considered a stress response that can be induced by intrinsic and extrinsic insults, including oncogenic activation, oxidative and genotoxic stress, mitochondria dysfunction, irradiation and chemotherapeutic agents. Senescence can be induced by various stressors and physiological states as replicative senescence (after many cycles, cells naturally stop), premature senescence (due to stressors), senescence involved in physiological processes. Senescence cells have both beneficial and detrimental effects on the organism. It has beneficial outcomes, especially during the early stages of development. Senescence occurs in many different locations during the development of the mammalian embryo and is responsible for the appropriate tissue remodeling and the elimination of unwanted cells as the tissues develop. It’s also responsible for beneficial outcomes on the adult organism, regulating proper wound healing by limiting the development of fibrotic tissue. According to geroscience, aging is a greatest risk factor for many diseases and conditions, so targeting the aging process will have an impact on human health. Senescence may be targeted with druggable therapeutic targets. 3