Linking functional decline of telomeres, mitochondria and stem cells during ageing

Abstract

The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signalling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere 'capping' function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, 'stemness' and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders.

Figure 1. Haematopoietic stem cells experience functional decline with ageing

Major differences between young (left) and old (right) haematopoietic stem cells (HSCs) are shown, exemplifying general mechanisms that may occur with age in stem cells, including decreased regenerative potential and dysregulated differentiation. Cell-extrinsic and cell-intrinsic factors contribute to the overall functional decline of ageing HSCs. Although the self-renewal capacity might be increased in aged HSCs, there is decreased functional regenerative capacity, particularly under stress conditions. Importantly, aged HSCs have an altered differentiation programme with reduced output of common lymphoid progenitors (CLPs), whereas common myeloid progenitors (CMPs) are produced at the same rate as by young HSCs. The decrease in numbers of CLPs and mature B and T cells (‘immunosenescence’) is in contrast to the increased frequency of common granulocyte–macrophage progenitors (GMPs) and, consequently, granulocytes and macrophages. Numbers of megakaryocyte–erythrocyte progenitors (MEPs) are not altered. Possible cell-extrinsic alterations relevant for HSC function include altered stromal compositions and altered cytokine profiles that favour specific differentiation programmes such as decreased lymphopoiesis and increased myelopoiesis. Other age-related changes could affect osteoblast and endothelial cells that have been shown to modulate HSC function. The relevance of systemic factors in modulating stem-cell function has been shown in parabiosis studies: the regenerative capacity of muscle satellite cells in aged mice was increased by exposure to the circulatory system of young mice through the restoration of Delta–Notch signalling. LRPs, lineage-restricted progenitors.

Figure 2. Telomerase knockout mice with dysfunctional telomeres develop premature ageing

Telomerase knockout mice (G₁) are viable, with intact chromosomes, and have minor physiological abnormalities in the case of long telomeres (top image; arrow); however, with advanced age, they develop degenerative symptoms sooner than do age-matched mice with wild-type Terc . Continuous interbreeding of telomerase knockout mice leads to subsequent generations of mice (G₂, G₃ and so on) with telomeres of decreasing length. Mice with dysfunctional telomeres have chromosomal abnormalities (bottom image; arrows point to loss of telomere signal, resulting in fused chromosomes), and they develop multiple ageing-associated degenerative disorders in highly proliferative organs, as well as in post-mitotic tissues. Highly proliferative organs such as the intestine, skin and testes are characterized by atrophic changes indicating stem-cell-based failure. Functional decline in post-mitotic tissues (such as cardiomyopathy) and age-associated metabolic changes (such as insulin resistance) have been noted in mice with dysfunctional telomeres. Such mice have a shortened lifespan and a modest increase in cancer, in line with the role of telomeres in preventing illegitimate recombination events.

Figure 3. A model of interaction between DNA damage, p53 activation and mitochondrial dysfunction

In this model, genotoxic stress brought about by telomere attrition, impaired DNA repair, ultraviolet (UV) radiation, ionizing radiation (IR), chemicals, ROS and other mechanisms activates p53 and induces cellular growth arrest (in proliferating compartments), senescence or apoptosis. We also propose that p53 can impair mitochondrial function either directly or indirectly (through regulation of ROS-detoxifying enzymes). This p53-mediated mitochondrial dysfunction triggers a cycle of DNA damage, p53 activation, mitochondrial compromise and increased ROS levels leading to additional DNA damage, and so on. The mitochondrial compromise could contribute to organ dysfunction through decreased ATP generation, as well as changes in mitochondrial metabolism. The interplay between p53 and other pathways implicated in ageing is also indicated. Caloric restriction (CR) activates SIRT1, which decreases p53 activity. Also, SIRT1 (and possibly SIRT6) activates PGC-1α and boosts mitochondrial biogenesis. PGC-1α increases antioxidant defence through upregulation of antioxidants, whereas p53 has been shown to increase or decrease the expression of antioxidants depending on cellular ROS concentrations. BMI1 loss has been shown to induce mitochondrial dysfunction directly and induce upregulation of p16/ARF (refs 30, 32). ARF increases p53 activity through interaction with MDM2, the negative regulator of p53.