What is Aging?
From Developmental Biology, 6th edition:
Aging can be defined as the time-related deterioration of the physiological functions necessary for survival and fertility.
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From WHO:
At the biological level, aging results from the impact of the accumulation of a wide variety of molecular and cellular damage over time. This leads to a gradual decrease in physical and mental capacity, a growing risk of disease and ultimately death
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From Wikipedia:
Aging is the process of becoming older. In humans, aging represents the accumulation of changes in a human being over time and can encompass physical, psychological, and social changes. Aging increases the risk of human diseases such as cancer, Alzheimer's disease, diabetes, cardiovascular disease, stroke and many more.
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Aging Theories
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Modern biological theories of human aging fall into two main categories: programmed aging and damage (or error) theories.
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Damage Theory: This concept suggests that aging results from the accumulation of damage, such as DNA oxidation, which leads to the failure of biological systems over time. Damage-related factors include both internal and environmental stressors that cause cumulative harm at various levels of an organism's physiology.
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Programmed Aging Theory: This theory proposes that aging is driven by intrinsic biological processes, such as epigenetic regulation (e.g., DNA methylation). Programmed aging follows a biological timetable, potentially an extension of the mechanisms that regulate childhood growth and development. These processes influence gene expression, affecting maintenance, repair, and defense systems, ultimately contributing to aging.
Cellular Senescence:
Cellular senescence is a process in which cells cease dividing and undergo distinct phenotypic changes, including significant chromatin remodeling, alterations in their secretome, and activation of tumor-suppressor mechanisms.
The term senescence was first introduced by Hayflick and Moorhead to describe the irreversible growth arrest observed in human diploid cell strains after extensive serial passaging in culture. This specific type of senescence, known as replicative senescence, was later linked to telomere attrition—a process that leads to chromosomal instability and promotes tumorigenesis. This discovery supported the original hypothesis that senescence serves as a protective mechanism against the uncontrolled proliferation of damaged cells.
Subsequent research has further established cellular senescence as a crucial safeguard against cancer. Emerging evidence suggests that its physiological role extends beyond tumor suppression, contributing to key biological processes such as embryonic development, wound healing, tissue repair, and organismal aging.
Cellular senescence and aging
Senescent cells progressively accumulate in the tissues and organs of humans, primates, and rodents with age.
One possible explanation is that the rate of senescent cell production increases over time. Supporting this idea, several studies have shown that various stimuli capable of inducing senescence also rise with aging. If cellular stressors collectively drive senescence, their accumulation would take a prolonged period.
Alternatively, the efficiency of senescent cell clearance may decline with age. This process is likely impacted in aging humans and rodents, as the immune system undergoes a series of complex changes in both innate and adaptive immunity, ultimately leading to age-associated immunodeficiency. A key aspect of this decline may be a reduced ability to eliminate senescent cells. Indeed, age-related dysfunction of hematopoietic stem cells compromises immune function, which could contribute to the systemic accumulation of senescent cells in later life.
Moreover, emerging evidence suggests that senescence is not a static state but rather a dynamic process, further influencing its role in aging and disease progression.
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How cellular senescence promotes age-related tissue dysfunction
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One scenario is that cellular senescence contributes to the overall decline in tissue regenerative potential that occurs with ageing. This idea is supported by the observation that progenitor cell populations in both skeletal muscle and fat tissue of BubR1 progeroid mice are highly prone to cellular senescence.
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In addition to acting on stem cells in a cell-autonomous fashion by establishing a persistent growth arrest, senescence could act to disrupt the local stem-cell niche non-autonomously through the Senescence-Associated Secretory Phenotype (SASP).
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Other SASP-based mechanisms may also contribute to tissue dysfunction. For example, proteases chronically secreted by senescent cells may perturb tissue structure and organization by cleaving membrane-bound receptors, signalling ligands, extracellular matrix proteins or other components in the tissue microenvironment.
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In addition, other SASP components, including IL-6 and IL-8, may stimulate tissue fibrosis in certain epithelial tissues by inducing EMT.
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Chronic tissue inflammation, which is characterized by infiltration of macrophages and lymphocytes, fibrosis and cell death, is associated with ageing and has a causal role in the development of various age-related diseases. One idea, which remains untested, is that senescent cells that accumulate with ageing and that are present at sites of age-related pathologies promote this type of inflammation through the proinflammatory growth factors, cytokines and chemokines they secrete. These may include GM-CSF, GROα, IL-1, IL-6, IL-8, macrophage inflammatory proteins (MIPs), as well as monocyte chemo-attractant proteins (MCPs). Together with matrix metalloproteinases, proinflammatory SASP components are thought to create a tissue microenvironment that promotes survival, proliferation and dissemination of neoplastic cells, which may explain, at least in part, why cancer rates markedly increase beyond middle age.
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Finally, the SASP may intensify age-related tissue deterioration through paracrine senescence, a recently discovered mechanism by which senescent cells spread the senescence phenotype to healthy neighbouring cells through secretion of IL-1β, TGFβ and certain chemokine ligands.
Senescence is a multi-step evolving process
It was known that cells from old individuals display a typical transcriptional signature, different from that of young counterparts. It was also known that fibroblasts from old donors have shortened telomeres as well as dysfunctional mitochondria and higher levels of oxidative stress.
However, senescence can be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify.
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The initiating step is the transition of temporal to stable cell-cycle arrest, which typically involves prolonged inhibition of Cdk–cyclin activity by p21, p16Ink4a, or both. A change in p53 expression from intermittent to continuous may be a critical event in the transition from temporal to persistent growth arrest.
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For the progression to full senescence, it seems that lamin B1 downregulation triggers both global and local modifications in chromatin methylation. Some mammalian cell types form regions of highly condensed chromatin called senescence-associated heterochromatin foci (SAHFs). SAHFs, which are enriched in chromatin modifications such as S83-HP1γ, HIRA, ASF1, macroH2A, H3K9me3 and γH2AX, sequester genes implicated in cell-cycle control, a phenomenon that seems to
reinforce the senescence-associated growth arrest. Among the assortment of upregulated genes is a prominent subset of genes that encode secreted proteins, including cytokines and chemokines with proinflammatory properties, as well as various growth factors and proteases that together alter tissue structure and function. Collectively, these factors are referred to as the senescence-associated secretory phenotype (SASP) or senescence-messaging secretome (SMS).
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Senescent cells continue to evolve even after extended periods of culture, thereby progressing to a stage that has been termed ‘deep’ or ‘late’ senescence. This phenomenon is evidenced by a dramatic increase in the transcription of transposable elements, including members of the L1, ALU and SVA transposon families, which occur several months after senescence onset. These newly synthesized retrotransposon transcripts can indeed engage in active transposition and accumulate in late-senescent cell genomes. Increased retrotransposon activity is associated with senescence-associated opening of gene-poor heterochromatic regions where these elements reside. A second process driving continued change in senescent cells is characterized by the extrusion of chromatin into the cytoplasm, resulting in the formation of cytoplasmic chromatin fragments (CCFs).
Rejuvenation:
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​Rejuvenation has long been a perennial dream—but is it possible? The answer is YES.
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The human longing for eternal youth is universal and timeless. In ancient times, people sought it through religion. During the Middle Ages, alchemists—part mystics, part proto-chemists—attempted to create a mysterious elixir of eternal youth, a potion believed to grant indefinite vitality to those who dared to drink it. Today, science may have uncovered the real biological fountain of rejuvenation—the cytoplasm of the oocyte.
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The Discovery of Biological Rejuvenation
The journey toward biological rejuvenation began in the early 1960s when John Gurdon and his collaborators discovered animal cloning in frogs. Three decades later, in 1996, mammalian cloning was achieved with the birth of Dolly the sheep, followed by the cloning of other mammalian species. These breakthroughs demonstrated that the cytoplasm of a mature oocyte contains molecules capable of reprogramming a somatic nucleus into an embryonic state, enabling the development of a new organism. Scientists hypothesized that the oocyte's cytoplasm must contain a complex constellation of reprogramming factors essential for resetting cellular age.
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