Targeting Mitochondria to Control Ageing and Senescence

Abstract

Ageing is accompanied by a progressive impairment of cellular function and a systemic deterioration of tissues and organs, resulting in increased vulnerability to multiple diseases. Here, we review the interplay between two hallmarks of ageing, namely, mitochondrial dysfunction and cellular senescence. The targeting of specific mitochondrial features in senescent cells has the potential of delaying or even reverting the ageing process. A deeper and more comprehensive understanding of mitochondrial biology in senescent cells is necessary to effectively face this challenge. Here, we discuss the main alterations in mitochondrial functions and structure in both ageing and cellular senescence, highlighting the differences and similarities between the two processes. Moreover, we describe the treatments available to target these pathways and speculate on possible future directions of anti-ageing and anti-senescence therapies targeting mitochondria.

Keywords: ageing; cellular senescence; mitochondrial targeting; novel therapeutic approaches.

Figure 1

Cellular senescence is a terminal state of proliferation arrest in response to stressors or damages. Classic markers of cellular senescence are increased cell size, development of a senescence-associated secretory phenotype (SASP), chromatin remodelling, increase (↑) in the lysosomal compartment and autophagy, and mitochondrial alterations. Created with BioRender.com.

Figure 2

Mitochondrial dysfunctions are a hallmark of both ageing and cellular senescence and represent crucial targets in treating ageing-associated diseases. (A) Both aged and senescent cells are characterised by modifications in the mitochondrial network, dynamics, and interactions between the organelle and the rest of the cell. However, differences can be observed between the two conditions. In particular, modifications in the mitochondria-to-nucleus retrograde responses can induce different epigenetic changes in senescent versus old cells and modulate signal transcription pathways, such as the mitochondrial unfolded protein response (UPRmt), differently. Mitochondrial DNA (mtDNA) release, moreover, can be detected and cause inflammation in both conditions, but its role is particularly relevant as part of the senescence-associated secretory phenotype (SASP). (B) Most mitochondrial functions are similarly defective or altered in aged and senescent cells. Inefficient mitochondrial respiration results in impaired metabolism, a drop in NAD⁺ levels, and ROS production. Calcium and ROS accumulation might cause increased susceptibility to the mitochondria permeability transition pore (mPTP) opening and apoptosis. Arrows indicate increase (↑) and decrease (↓) of the correspondent feature. Created with BioRender.com.