The mechanism of ageing: primary role of transposable elements in genome disintegration

Abstract

Understanding the molecular basis of ageing remains a fundamental problem in biology. In multicellular organisms, while the soma undergoes a progressive deterioration over the lifespan, the germ line is essentially immortal as it interconnects the subsequent generations. Genomic instability in somatic cells increases with age, and accumulating evidence indicates that the disintegration of somatic genomes is accompanied by the mobilisation of transposable elements (TEs) that, when mobilised, can be mutagenic by disrupting coding or regulatory sequences. In contrast, TEs are effectively silenced in the germ line by the Piwi-piRNA system. Here, we propose that TE repression transmits the persistent proliferation capacity and the non-ageing phenotype (e.g., preservation of genomic integrity) of the germ line. The Piwi-piRNA pathway also operates in tumorous cells and in somatic cells of certain organisms, including hydras, which likewise exhibit immortality. However, in somatic cells lacking the PiwipiRNA pathway, gradual chromatin decondensation increasingly allows the mobilisation of TEs as the organism ages. This can explain why the mortality rate rises exponentially throughout the adult life in most animal species, including humans.

Accelerated Senescence of Cancer Stem Cells: A Failure to Thrive or a Route to Survival?

“…Similarly, arrest in late S-and G2M phase was reported after Doxorubicin treatment in p53 mutant cancer cells [54]. This feature may therefore be equally required for any senescence causing release from silencing and subsequent activation of TE nested in constitutive heterochromatin as retrotransposition was found in replicative cell senescence [55,56]. In particular, under-replication may cause de-repression of TE genes and result in the epigenetic activation of the developmental genes in the poised chromatin regions [30] enabling the reprogramming by senescence.…”

Somatizing the transposons action

“…These processes appear to be directly related to the accumulation of mutations, which results in cell death or dysfunction. 59,60,61 Some regulatory pathways and essential cellular processes are affected during senescence. The epigenetic regulatory mechanisms seem to undergo large alterations, such as the loss of methylated regions and histone modifications.…”

“…Studies relating the decline of heterochromatin to the activation of TEs during aging have been performed in different models, such as Caenorhabditis elegans, Drosophila melanogaster, mice and the cell cultures of other mammals. 61,62 In Drosophila, the reduction of heterochromatin and the activation of somatic transposition of retrotransposons were detected in body fat and this high transposition rate was correlated with the breaking of DNA molecules in this tissue. 63 Moreover, the activation of TEs in Drosophila brains during aging and the increase in somatic transposition seem to be related to the neuronal decline of older flies.…”

Epigenetics of Carcinogenesis

“…Прогрессирующее гипомети-лирование генома человека при старении происхо-дит преимущественно в последовательностях транс-позонного происхождения. При этом мобилизация ТЕ приводит к геномной нестабильности, ведущей к дегенеративным процессам и раку [13]. Количест-во компонентов ТЕ, как транскриптов, так и белков в неоплазмах выше по сравнению с нормальной тканью.…”

“…В мужских по-ловых клетках L1 ингибируются сложной системой, включающей piРНК, которая в конечном счете мети-лирует L1 [9]. При этом нарушение регуляции PiwipiРНК путей обнаруживается в опухолевых клетках [13]. В эмбриональных стволовых клетках унасле-дованное метилирование L1 поддерживается ДНК-метилтрансферазами DNMT1, DNMT3A, DNMT3B.…”