Роль сиртуинов в эпигенетической регуляции и контроле старения

Достижения современного здравоохранения в развитых странах позволили увеличить продолжительность жизни, из­-за чего все более актуальным становится сохранение активного долголетия. С момента открытия белки семейства сиртуинов рассматривались в качестве значимых регуляторов физиологических процессов, ассоциированных со старением. Сиртуины проявляют деацетилазную, деацилазную, АДФ­рибозилтрансферазную активность и модифицируют множество белковых субстратов, включая компоненты хроматина и регуляторные белки. Столь многофакторная система регуляции затрагивает ряд процессов, таких как клеточный метаболизм, функции митохондрий, эпигенетическую регуляцию, репарацию ДНК и прочие. Неудивительно, что активность белков­сиртуинов затрагивает проявление классических признаков старения организма: клеточное старение, нарушения метаболизма, митохондриальную дисфункцию, геномную нестабильность и нарушение эпигенетической регуляции. Непосредственное изменение активности сиртуинов в клетках человека также рассматривается в качестве маркера старения и вовлечено в генез различных возраст-­зависимых патологических состояний. Кроме того, экспериментальные данные, полученные на модельных животных, а также результаты популяционных геномных исследований позволяют предположить влияние сиртуинов на продолжительность жизни. Вместе с тем многообразие функций сиртуинов и биохимических субстратов делает крайне нетривиальным выявление причинно-­следственных связей и непосредственной роли сиртуинов в контроле функционального состояния организма. Однако влияние сиртуинов на эпигенетическую регуляцию экспрессии генов в ходе старения и при патологиях – один из наиболее важных аспектов поддержания гомеостаза органов и тканей. Представленный обзор посвящен разнообразию белков­-сиртуинов у человека и модельных животных. Помимо краткого описания основных ферментативных и биологических активностей сиртуинов, рассматривается роль сиртуинов в эпигенетической регуляции структуры хроматина, в том числе в контексте развития нестабильности генома, ассоциированной со старением. Проведен критический анализ работ по исследованию функциональной связи сиртуинов и долголетия, а также влияния сиртуинов на ассоциированные со старением патологические процессы, такие как хроническое воспаление, фиброз и нейровоспаление.

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