There are 9 hallmarks of ageing; genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.
Genomic instability and telomere attrition are hallmarks of ageing. Endogenous or exogenous agents can stimulate a variety of DNA lesions that are schematically represented on a single chromosome. Excessive DNA damage or insufficient DNA repair favours the ageing process. This could affect nuclear or mitochondrial DNA. Elimination of damaged cells and telomerase reactivation help extend human health span.
Epigenetic alterations are another hallmark for ageing. These are alterations in acetylation and methylation of DNA or histones, as well as of other chromatin-associated proteins. These may induce epigenetic changes that contribute to the ageing process. Epigenetic drugs help extend human health span.
Another hallmark of ageing is loss of proteostasis which is the unfolding of proteins due to exogenous and endogenous stress. It also impairs proper folding during protein synthesis. Unfolded proteins are usually refolded by heat-shock proteins or targeted to destruction by the ubiquitin-proteasome or lysosomal (autophagic) pathways. Failure to refold or degrade unfolded proteins can lead to their accumulation and aggregation, resulting in proteotoxic effects. Activation of chaperones and protease systems help extend human health span.
Deregulated nutrient-sensing is the overview of the somatroph axis involving growth hormone (GH) and the insulin/insulin growth factor 1 (IGF-1) signalling pathway and its relationship to dietary restriction and ageing. Molecules that favour ageing are GH, IGF-1, PI3K, Akt and mTOR. Whereas PTEN, FOXO, AMPK, Sirt1 and PGC-1a are all molecules with anti-ageing properties. Inhibition of DR, IIS and mTOR help extend human health span, as well as the activation of AMPK and sirtuins.
Stress signals and defective mitochondrial function generate reactive oxygen species (ROS) that, below a certain threshold, induce survival signals to restore cellular homeostasis. However, at higher continued levels, it can contribute to ageing through mitochondrial dysfunction. Mitohormetics and mitophagy help extend human health span.
Cellular senescence prevents the proliferation of damaged cells, in young organisms, thus protecting from cancer and contributing to tissue homeostasis. In old organisms, the pervasive damage and the deficient clearance and replenishment of senescent cells results in their accumulation. This has a number of deleterious effects on tissue homeostasis, that contribute to ageing. Clearance of these senescent cells help extend human health span.
The final hallmarks of ageing are stem cell exhaustion and altered intracellular communication. Consequences of the exhaustion of haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), satellite cells and intestinal epithelial stem cells (IESCs) include anaemia, osteoporosis, loss of muscle fibres and intestinal function. Neurohormonal signalling, such as renin-angiotensin, adrenergic, insulin-IGF1 signalling, tend to be deregulated. Inflammatory reactions increase, due to accumulation of pro-inflammatory tissue damage, failure to effectively clear pathogens and dysfunctional host cells, the propensity of senescent cells to secrete pro-inflammatory cytokines. Stem cell-based therapies help extend human health span with stem cell exhaustion whereas anti-inflammatory drugs and blood-borne juvenile factors allow extending the human health span for altered intracellular communication.
Pharma and Biotech Advances 