Ageing

In Caenorhabditis elegans, mitochondrial activity as measured by the frequency of the mitochondrial flash in young adult animals is a powerful predictor of lifespan across genetic, environmental and stochastic factors.

This study shows that ageing satellite cells undergo an irreversible transition from a quiescent to a pre-senescent state that results in the loss of muscle regeneration in sarcopenia; furthermore, increased expression of p16^INK4a is identified as a common feature of senescent satellite cells.

This study identifies a shift from canonical to non-canonical Wnt signalling in ageing haematopoietic stem cells (HSCs); elevated expression of Wnt5a in aged HSCs has a causal role in stem-cell ageing, and this is mediated by the small Rho GTPase Cdc42.

In Caenorhabditis elegans, genome instability in the form of exogenous and endogenous DNA damage in germ cells evokes elevated heat- and oxidative-stress resistance in somatic tissues; this is mediated by MPK-1, which triggers the induction of putative secreted peptides associated with innate immunity, leading to activation of the ubiquitin–proteasome system.

Mutations in mitochondrial DNA (mtDNA) accumulate at a higher rate than mutations in nuclear DNA, and although somatic mtDNA mutations are known to be involved in mammalian ageing, the role of germline mutations in this process is unclear: here germline-transmitted mtDNA mutations are shown to be associated with ageing and brain malformations, and maternally transmitted mtDNA mutations may thus influence both development and ageing.

Naked mole rats seem almost entirely protected from developing cancer, and this can now, at least in part, be explained by the production of a unique high-molecular-mass form of hyaluronan, a component of the extracellular matrix; together with an increased sensitivity of naked mole-rat cells to hyaluronan signalling, this form protects its cells from oncogenic transformation.

Mitochondrial ribosomal proteins have been identified as longevity regulators in C. elegans and mammalian systems, their role in longevity is linked to mitonuclear protein imbalance and the mitochondrial unfolded protein response.

Activation of IKK-β and NF-κB in the hypothalamus of mice is shown to accelerate the ageing process, leading to shortened lifespan; inhibition of hypothalamic or brain IKK-β and NF-κB delays ageing and increases lifespan, and NF-κB activation results in a reduction of GnRH levels, whereas NF-κB inhibition leads to GnRH-induced neurogenesis to mediate ageing retardation.

A role is demonstrated for miR-34a, a microRNA that is upregulated in the ageing heart; miR-34a downregulates PNUTS, a protein that protects cardiomyocytes and telomeres, silencing of miR-34a is therefore a promising therapeutic target.

During normal ageing a low rate of division of pre-existing cardiomyocytes, rather than progenitor cells, is responsible for cardiomyocyte genesis; this process is increased fourfold during myocardial infarction.

Vacuolar acidity in yeast is shown to decline with age, and preventing this decrease suppresses mitochondrial dysfunction and extends the lifespan of yeast.

In the Drosophila testis, IGF-II messenger RNA binding protein (Imp) is shown to promote stem-cell niche maintenance by stabilizing unpaired (upd) RNA; Imp levels decrease in the hub cells of older males, owing to regulation by the microRNA let-7.

The conserved microRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila, providing a molecular link between ageing and neurodegeneration.

Activating AMPK or inactivating calcineurin slows ageing in worms and increases their lifespan. Here it is shown that inhibition of CRTC-1 is required for these life-extending effects. CRTC-1 is the only worm member in the family of CREB-regulated transcriptional co-activators, or CRTCs, and, like the mammalian family members, CRTC-1 interacts with a worm homologue of the CREB transcription factor (CRH-1). Eliminating crtc-1 increases lifespan in a crh-1-dependent manner, as does elimination of crh-1 alone. Downregulation of components in the CRTC/CREB pathway has previously been shown to confer health benefits to mice, complementing their lifespan effects in worms.

Here it is shown that reactivation of endogenous telomerase activity in mice extends telomeres, reduces DNA damage signalling, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease and the reversal of damage observed here support the development of regenerative strategies designed to restore telomere integrity.

The insulin/IGF-1 signalling (IIS) pathway is involved in various biological processes, including regulation of longevity. In the worm Caenorhabditis elegans, the transcription factor DAF-16a, one of two isoforms, has a major role in this pathway, regulating longevity, stress response and dauer diapause. These authors describe a new isoform, DAF-16d/f, which is also important in the regulation of lifespan. The DAF-16 isoforms functionally cooperate to fine-tune IIS-mediated processes in the context of a whole organism.

Age-associated changes in stem cell supportive niche cells are shown to deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment.