Basics of cellular aging and
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Cellular ageing and theories apoptosis
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Basics of cellular aging and
- 1. Cellular Ageing and ApoptosisMallappa Shalavadi Asst. Prof., Dept. of Pharmacology HSK College of Pharmacy, Bagalkot-587101
- 2. CELLULAR AGING Shakespear - ‘Seven ages of man’ • It begins at the moment of conception • Involve the differentiation • Maturation of the organism and its cells • At some variable point in time leads progressive loss of functional capacity characteristic of senescence • Ends in death
- 3. • Cellular aging is the result of a progressive decline in the proliferative capacity and life span of cells and the effects of continuous exposure to exogenous factors that cause accumulation of cellular and molecular damage.
- 4. • Normal life span - brain cells live as long as you do and the neurons in CNS once formed by age 6 do not divide. RBC live only 120 days • Gender differences - women live longer than men 78 vs 81 years may be due to genetic superiority • Different speeds with which mortality increases with age correspond to different maximum life span among species. • For example, a mouse is elderly at 2 years, while a human is elderly at 80 years.
- 7. • Shortening of Telomeres • Accumulation of aging pigments- Lipofuscin accumulation • Accumulation of free radicals • Weakened immune system • Decrease in rate of cell division
- 8. Extracellular changes • The changes occuring in the intercellular spaces and in the lumen of blood vascular system are examples Dementia • Dementia is a serious loss of cognitive ability .
- 10. Atherosclerosis
- 13. Changes in collagen There is an increase in the amount of collagen proteins deposition in the intercellular spaces. This influences the permeability of cell membranes, affects the speed of diffusion of substances in and out and significantly influences the process of aging.
- 14. Wrinkles and Ageing • Wrinkles are a by-product of the aging process. • With age, skin cells divide more slowly, and the inner layer, called the dermis, begins to thin. • The network of elastin (the protein which causes skin to stretch) and collagen fibers (the major structural proteins in the skin), which support the outer layer. • With aging, skin also loses its elasticity, is less able to retain moisture, oil-secreting glands are less efficient and the skin is slower to heal.
- 17. Mechanisms of cellular aging. Genetic factors and environmental insults combine to produce the cellular abnormalities characteristic of aging
- 19. Genomic Instability • One common denominator of aging is the accumulation of genetic damage throughout life • Premature aging diseases, such as Werner syndrome.
- 21. Telomere Attrition o All normal cells have a limited capacity for replication, and after a fixed number of divisions cells become arrested in a terminally non-dividing state, known as replicative or cellular senescence. o How dividing cell count their divisions? o Each cell division there is a incomplete replication of chromosome ends [telomere shortening] which ultimately arrest cell cycle. o Telomeres are short repeated sequences of DNA [TTAGGG] present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation.
- 23. Finite population doublings of primary human fibroblasts derived from a newborn, a 100-year-old person, and a 20-year-old patient with Werner's syndrome. The ability of cells to grow to a confluent monolayer decreases with increasing population-doubling levels.
- 24. • The lengths of the telomeres are normally maintained by nucleotide addition mediated by an enzyme called telomerase. • Telomerase - specialized RNA-protein complex - uses its own RNA as a template for adding nucleotides to the ends of chromosomes. • Telomerase activity is expressed in germ cells and is present at low levels in stem cells, but it is usually absent in most somatic tissues. • Cancer cells- telomerase is reactivated and telomeres are not shortened, suggesting that telomere elongation might be an important-possibly essential-step in tumor formation.
- 26. Telomerase directs RNA template-dependent DNA synthesis, in which nucleotides are added to one strand at the end of a chromosome. The lagging strand is presumably filled in by DNA polymerase α.
- 27. Epigenetic Alterations • Epigenetic changes involve 1. Alterations in DNA methylation patterns 2. Posttranslational modification of histones 3. Chromatin remodeling • In humans and other mammals, DNA methylation levels can be used to accurately estimate the age of tissues and cell types, forming an accurate epigenetic clock. • A longitudinal study of twin children showed that, between the ages of 5 and 10, there was divergence of methylation patterns due to environmental rather than genetic influences. • There is a global loss of DNA methylation during aging.
- 28. • Histone methylation meets the criteria for a hallmark of aging in invertebrates. • Deletion of components of histone methylation complexes extends longevity.
- 29. • Chromatin remodeling is the rearrangement of chromatin from a condensed state to a transcriptionally accessible state, allowing transcription factors or other DNA binding proteins to access DNA and control gene expression. • Global heterochromatin loss and redistribution, which constitute characteristic features of aging • Overexpression of this heterochromatin protein extends longevity in flies and delays the muscular deterioration characteristic of old age
- 30. Loss of Proteostasis • Aging and some aging-related diseases are linked to impaired protein homeostasis or proteostasis
- 31. Deregulated Nutrient Sensing • Decreased signaling of IGF-1 receptor- Decreased caloric intake- promotes the ageing.
- 32. Mitochondrial Dysfunction • As cells and organisms age, the efficacy of the respiratory chain tends to diminish, thus increasing electron leakage and reducing ATP generation • The relation between mitochondrial dysfunction and aging has been long suspected, but dissecting its details remains as a major challenge for aging research.
- 33. Role of Free Radicals
- 34. Stem Cell Exhaustion • The decline in the regenerative potential of tissues is one of the most obvious characteristics of aging • Hematopoiesis declines with age, resulting in a diminished production of adaptive immune cells and in an increased incidence of anemia and myeloid malignancies Hematopoietic stem cells (HSCs), Mesenchymal stem cells (MSCs), Intestinal epithelial stem cells (IESCs)
- 35. Altered Intercellular Communication • Beyond cell-autonomous alterations, aging also involves changes at the level of intercellular communication, be it endocrine, neuroendocrine, or neuronal
- 36. Functional Interconnections between the Hallmarks of Aging
- 37. Interventions that Might Extend Human Health span
- 39. APOPTOSIS
- 40. • Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes capable of degrading the cells' own nuclear DNA and nuclear and cytoplasmic proteins. • Programmed Cell Death • Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, "falling off"). • Between 50 and 70 billion cells die each day due to apoptosis in the average human adult. For an average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die a day
- 46. The extrinsic (death receptor-initiated) pathway of apoptosis
- 47. The intrinsic (mitochondrial) pathway of apoptosis
- 48. The Execution Phase • Ececutioner caspase –Caspase-3 and 6 • Act on many cellular proteins with cytoskeleton and finally nucleus • In nucleus they distrups the proteins involved in transcription, DNA replication and DNA repair. • Caspase-3 activates DNase
- 49. Removal of Dead Cell • At early stage of apoptosis, dying cells secretes soluble factors that recruit the Phagocytes. • This lead prompt clearance of the apoptotic cells before they undergo secondary necrosis and release their secondary cellular contents which can lead inflammation.
Notas del editor
- SDH=Succinate dehydrogenase AC Pase=Acid phosphatase
- Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the gene, WRN, the only gene currently attributed to cause Werner syndrome.[11][12] WRN, which lies on chromosome 8 in humans,[23] encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQhelicases. RecQ helicases are a special type of helicase that function at unique times during DNA repair of doubled Werner syndrome (WS), also known as "adult progeria",[1] is a rare, autosomal recessive disorder[2] which is characterized by the appearance of premature aging stranded breaks, which are a form of DNA damage that results in a break of both strands of DNA. Thus, RecQ helicases are important for maintaining DNA stability, and loss of function of these helicases has important implications in the development of Werner syndrome.
- Spindle checkpoint From Wikipedia, the free encyclopedia Jump to navigationJump to searchDuring the process of cell division, the spindle checkpoint prevents separation of the duplicated chromosomes until each chromosome is properly attached to the spindle apparatus. In order to preserve the cell's identity and proper function, it is necessary to maintain the appropriate number of chromosomes after each cell division. An error in generating daughter cells with fewer or greater number of chromosomes than expected (a situation termed aneuploidy), may lead in best case to cell death, or alternatively it may generate catastrophic phenotypic results.[1] Examples include: In cancer cells, aneuploidy is a frequent event, indicating that these cells present a defect in the machinery involved in chromosome segregation, as well as in the mechanism ensuring that segregation is correctly performed. In humans, Down syndrome appears in children carrying in their cells one extra copy of chromosome 21, as a result of a defect in chromosome segregation during meiosis in one of the progenitors. This defect will generate a gamete (spermatozoide or oocyte) with an extra chromosome 21. After fertilisation, this gamete will generate an embryo with three copies of chromosome 21. The mechanisms verifying that all the requirements to pass to the next phase in the cell cycle have been fulfilled are called checkpoints. All along the cell cycle, there are different checkpoints. The checkpoint ensuring that chromosome segregation is correct is termed spindle assembly checkpoint (SAC), spindle checkpoint or mitotic checkpoint. During mitosis or meiosis, the spindle checkpoint prevents anaphase onset until all chromosomes are properly attached to the spindle. To achieve proper segregation, the two kinetochoreson the sister chromatids must be attached to opposite spindle poles (bipolar orientation).[2] Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. An adduct (from the Latin adductus, "drawn toward" alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all components.[1] The resultant is considered a distinct molecular species. Examples include the addition of sodium bisulfite to an aldehyde to give a sulfonate. It can just be considered as a single product resulting from direct addition of different molecules and constitutes all the reactant molecules' atoms.
- DNA methylation is a process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. [preventingtranscription of the genes into messenger RNA]
- histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes.[1][2] They are the chief protein components of chromatin, acting as spools around which DNA winds, and playing a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very long (a length to width ratio of more than 10 million to 1 in human DNA). For example, each human diploid cell (containing 23 pairs of chromosomes) has about 1.8 meters of DNA; wound on the histones, the diploid cell has about 90 micrometers (0.09 mm) of chromatin. When the diploid cells are duplicated and condensed during mitosis, the result is about 120 micrometers of chromosomes.[3]
- Endogenous and exogenous stress causes the unfolding of proteins (or impairs proper folding during protein synthesis). Unfolded proteins are usually refolded by heat-shock proteins (HSP) or are targeted to destruction by the ubiquitin-proteasome or lysosomal (autophagic) pathways. The autophagic pathways include recognition of unfolded proteins by the chaperone Hsc70 and their subsequent import into lysosomes (chaperone-mediated autophagy) or sequestration of damaged proteins and organelles in autophagosomes that later fuse with lysosomes (macroautophagy). Failure to refold or degrade unfolded proteins can lead to their accumulation and aggregation, resulting in proteotoxic effects.
- The bystander effect, or bystander apathy, is a social psychological phenomenon in which individuals are less likely to offer help to a victim when other people are present.
- The proposed nine hallmarks of aging are grouped into three categories. (Top) Those hallmarks considered to be the primary causes of cellular damage. (Middle) Those considered to be part of compensatory or antagonistic responses to the damage. These responses initially mitigate the damage, but eventually, if chronic or exacerbated, they become deleterious themselves. (Bottom) Integrative hallmarks that are the end result of the previous two groups of hallmarks and are ultimately responsible for the functional decline associated with aging.
- 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 and SnRK1 in yeast and plants, respectively. The mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene.[5][6][7]mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases The sirtuins (SIRT1–7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans. Mitophagy is the selective degradation of mitochondria by autophagy. Low-level oxidative stress induces an adaptive response commonly defined as hormesis; this type of stress is often related to reactive oxygen species (ROS) originating from the mitochondrial respiratory chain (mitochondrial hormesis ormitohormesis).