Hallmarks of cardiovascular ageing

Abdellatif, Mahmoud; Rainer, Peter P.; Sedej, Simon; Kroemer, Guido

doi:10.1038/s41569-023-00881-3

Cited by 80 publications

(36 citation statements)

References 447 publications

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“…The existence of evolutionarily conserved mechanisms underlying the selective degradation of mitochondria highlights the key physiological role of mitophagy. Mitochondrial dysfunction is a major hallmark of ageing 170,171 and targeting mitophagy through any of its metabolic regulators discussed in this review might prove to be a valid entry point to treat chronic age‐related disorders, including neurodegenerative and cardiovascular disease. Disturbance of neuronal metabolism in Drosophila mitophagy mutants can be rescued through metabolic interventions with deoxyribonucleosides and folic acid, 172 or nicotinamide supplementation 173 .…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Metabolic control of mitophagy

Zimmermann,

Madeo,

Diwan

et al. 2023

Eur J Clin Investigation

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Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process known as mitophagy, is vital for mitochondrial homeostasis and cell survival. The central role of mitochondria in cellular metabolism places mitochondrial removal at the interface of key metabolic pathways affecting the biosynthesis or catabolism of acetyl‐coenzyme A, nicotinamide adenine dinucleotide, polyamines, as well as fatty acids and amino acids. Molecular switches that integrate the metabolic status of the cell, like AMP‐dependent protein kinase, protein kinase A, mechanistic target of rapamycin and sirtuins, have also emerged as important regulators of mitophagy. In this review, we discuss how metabolic regulation intersects with mitophagy. We place special emphasis on the metabolic regulatory circuits that may be therapeutically targeted to delay ageing and mitochondria‐associated chronic diseases. Moreover, we identify outstanding knowledge gaps, such as the ill‐defined distinction between basal and damage‐induced mitophagy, which must be resolved to boost progress in this area.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Metabolic control of mitophagy

Zimmermann,

Madeo,

Diwan

et al. 2023

Eur J Clin Investigation

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“…At the cellular level, the decline in tissue integrity during aging has been associated with the accumulation of senescent cells (SCs) 3 along with stem cell exhaustion 1 and reduced immune competence 4,5 . Cellular senescence is a terminal state that has been implicated as a core cause of various age-related diseases, including cardiovascular diseases 6,7 , dementia 7,8 , and cancer 9,10 . This cellular state can be induced by DNA damage, oncogenic mutations, mitochondrial dysfunction, mechanical stress, or infections 11 .…”

Section: Introductionmentioning

confidence: 99%

CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging

Elyahu,

Feygin,

Pinkas

et al. 2024

Preprint

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Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases and, eventually, death. One prominent process in aging is the accumulation of senescent cells. Although the immune system has been recognized as crucial for the elimination of senescent cells, the associated mechanisms remain incompletely understood. Here we show that CD4 T cells differentiate into cytotoxic T lymphocytes (CTLs) in a senescent cell-rich environment and that a reduction in the senescent cell load, achieved using chemical senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4 CTLs in the context of late aging by selectively deleting the Eomes transcription factor in CD4 T cells resulted in the increased accumulation of senescent cells, profound physical deterioration, and a decreased life span. In liver cirrhosis, a model of localized chronic inflammation, CD4 CTL elimination increased the senescent load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4 CTLs in modulating tissue senescence and unveil a new aspect of age-related T-cell biology implicated in disease susceptibility and longevity.

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“…For example, it is yet to be clarified which heart cell types are determinant for DNA damage-linked heart pathology. In this context, the implication of cardiomyocytes has been highlighted (Abdellatif et al, 2023;Puente et al, 2014), while that of vasculature smooth muscle cells has been implicated but not explored exhaustively (Gray et al, 2015;Wu et al, 2023). Downstream to DNA damage, cell senescence impacts on vascular smooth muscle and endothelial cells, cardiomyocytes, and heart immune cells, and is associated with cardiovascular disease (Campisi & d'Adda di Fagagna, 2007).…”

Section: Introductionmentioning

confidence: 99%

Impact of diffused versus vasculature targeted DNA damage on the heart of mice depleted of telomeric factor Ft1

La Torre,

Centofante,

Nicoletti

et al. 2023

Aging Cell

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DNA damage is emerging as a driver of heart disease, although the cascade of events, its timing, and the cell types involved are yet to be fully clarified. In this context, the implication of cardiomyocytes has been highlighted, while that of vasculature smooth muscle cells has been implicated but not explored exhaustively. In our previous work we characterized a factor called Ft1 in mice and AKTIP in humans whose depletion generates telomere instability and DNA damage. Herein, we explored the effect of the reduction of Ft1 on the heart with the goal of comparatively defining the impact of DNA damage targeted to vasculature smooth muscle cells to that of diffuse damage. Using two newly generated mouse models, Ft1 constitutively knocked out (Ft1ko) mice, and mice in which we targeted the Ft1 depletion to the smooth muscle cells (Ft1sm22ko), it is shown that both genetic models display cardiac defects but with differences. Both Ft1ko and Ft1sm22ko mice display hypertrophy, fibrosis, and functional heart defects. Interestingly, Ft1sm22ko mice have early milder pathological traits that become manifest with age. Significantly, the defects of Ft1ko mice, including the alteration of the left ventricle and functional heart defects, are rescued by depletion of the DNA damage sensor p53. These results point to Ft1 deficiency as a driver of cardiac disease and show that Ft1 deficiency targeted to vasculature smooth muscle cells generates a pre‐pathological profile exacerbated by age.

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Hallmarks of cardiovascular ageing

Cited by 80 publications

References 447 publications

Metabolic control of mitophagy

Metabolic control of mitophagy

CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging

Impact of diffused versus vasculature targeted DNA damage on the heart of mice depleted of telomeric factor Ft1

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