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The science of ageing
Published in Michael Parker, Charlie James, Fundamentals for Cosmetic Practice, 2022
Our cells divide at a predetermined rate and have a predetermined life span as discussed in the programmed ageing theory. The replicative senescence theory was suggested by the anatomist Dr Leonard Hayflick in 1961 after he noted that human foetal cells can divide 40–60 times before being able to replicate no more and becoming senescent. The number of cell divisions a cell can undertake has been named after him due to this work as the Hayflick limit.
Oncogenesis and Metastasis
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Telomeres are DNA ‘buffers’ at the end of each chromosome.Stretches of repetitive DNA sequences that protect against degeneration.In rapidly dividing cells, telomeres may be ‘worn down’ and become insufficient to protect cells.At this critical length, cell division will cease— this is called the ‘Hayflick limit’.
Neoplasia
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Telomeres are repeating DNA sequences found at the ends of chromosomes which allow the DNA strand to fold back on itself forming a loop (binding to the complementary sequence on the opposite DNA strand), thus protecting the chromosome end from being sensed as a double-strand DNA break. Telomeres are also important in regulating the number of cell divisions of which a cell is capable, the so-called Hayflick limit (see Chapter 2). Each time a cell divides, the cell's DNA replicates, and the telomere repetitive sequence is shortened (as it is difficult to prime DNA synthesis from an end), until eventually most or all of the telomeric repetitive sequence is lost (preventing loop formation that usually protects the chromosome end) and the cell is incapable of further replication, bringing about cellular senescence. This does not apply to stem cells, because they contain a mechanism for lengthening telomeres, an enzyme called telomerase that contains its own RNA component that can prime DNA replication at the end of the chromosome. Aberrant expression of telomerase can immortalize tumour cells. Indeed, many tumours express increased or aberrant telomerase activity. This may open novel therapeutic approaches to cancer, with the development of telomerase-inhibiting drugs.
The role of mTOR in age-related diseases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zofia Chrienova, Eugenie Nepovimova, Kamil Kuca
Ageing can be defined as functional decline causing age-related diseases and eventually death. Several theories regarding the mechanism underlying ageing have been proposed, among which the Hayflick limit and the ROS theory are the most widely known. The Hayflick limit is based on a 1965 study showing that fibroblasts have a limited replicative lifespan due to telomere shortening during each replication193. However, this theory is not universally supported, since a clear correlation between telomere length and the maximal lifespan has not been observed194–196. The ROS theory was proposed by Harman in 1956197,198, who stated that “there had to be some common, some basic cause which is killing everything. Free radicals cause random damage, and depending on the type of radical, they can cause all kinds of damage from day one.” However, clinical trials have disproven this theory, since antioxidants have no effect on age-related diseases or mortality and do not extend lifespan. Indeed, lifespan can be extended without reductions in ROS199,200.
Drugs that target aging: how do we discover them?
Published in Expert Opinion on Drug Discovery, 2019
Cellular senescence (hereinafter, ‘senescence’) refers to a permanent state of arrested cell proliferation wherein a cell remains alive but fails to divide and reproduce. Senescent cells can be distinguished, both morphologically and through biomarkers, from either cells undergoing transient growth arrest (‘quiescence’) or terminally differentiated cells, which lose their ability to replicate once they have taken on a specialized function (e.g. red blood cells, neurons, etc.) [26]. Senescence was discovered by Leonard Hayflick and Paul Moorhead during experiments in the 1960s that uncovered the Hayflick Limit, i.e. the inability for cells to divide and reproduce more than a certain number of times in culture [27,28]. It was later determined that this type of senescence (termed ‘replicative senescence’) is a result of a DNA damage response triggered by telomere attrition during repeated replication that cannot be repaired by endogenous DNA repair machinery. Cellular senescence can also be induced in other ways, for example through mutations that produce activated oncogenes, elevated levels of reactive oxygen species (ROS), other (non-ROS producing) mitochondrial dysfunction, and DNA damage induced by ionizing radiation, genotoxic chemotherapies, or stalled replication or transcription forks; as well as through pathways that trigger derepression of the gene locus CDKN2A, leading to increased expression of the p16INK4a protein (hereinafter, ‘p16ʹ) [29].
Platelet-rich concentrate in serum-free medium enhances cartilage-specific extracellular matrix synthesis and reduces chondrocyte hypertrophy of human mesenchymal stromal cells encapsulated in alginate
Published in Platelets, 2019
Shani Samuel, Raja Elina Ahmad, Thamil Selvee Ramasamy, Puvanan Karunanithi, Sangeetha Vasudevaraj Naveen, Tunku Kamarul
PRC increased cell proliferation, which peaked at day 16. However, there was a decline in cell proliferation beyond that time, which could be attributed to various factors. This includes replicative senescence, whereby cells lose their potential to proliferate after a certain number of cell divisions, a phenomenon referred to as the hayflick limit [22,23]. Increased cell numbers could also result in contact dependent inhibition of cell proliferation [24,25]. The decrease in cell proliferation after day 16 in the PRC group as seen in our study corroborates with a previous study that showed a gradual decline in cell numbers in the PRP treated group after day 6. The cells were observed to have undergone morphological transformation and showed signs of cellular differentiation beyond day 6 [26], which could have contributed to the decrease in cell numbers. Thus, the transition to active cellular differentiation, which would arrest further proliferation, could also explain the observation in the present study. Another factor that may account for the decline in cell proliferation is poor diffusion of nutritive substances, particularly to the cells at center of the alginate beads. A previous study has shown an increase in the number of dead cells population in the center of 3D pellets, which has been speculated to be due to reduced access to nutrients and oxygen [27].