Tissue-specific aging: a tale of functional asymmetry

asymmetry is a fundamental aspect of all living beings. This also applies to single celled organisms that reproduce symmetrically into two identical halves; the cell that inherits the old pole, it grows at a slower rate, produces less offspring, and shows a decrease in overall cell viability (Stewart EJ et al., PloS Biol 2005; 2:e45). Functional asymmetry becomes clearly visible when one considers the dramatic differences between the immortal germ line and the disposable soma or between the countless cell types of multicellular organisms; most cells differ in their metabolic demands, replicative potential, and developmental origin or are exposed to distinct intrinsic and environmental hazards. However, what makes functional asymmetry more relevant for aging is that any unforeseen cellular mistake will also have asymmetric outcomes for human health e.g. the faulty repair of DNA lesions may have a much higher cost in one direction (e.g. stem cells) than in the other (e.g. hepatocytes). Moreover, functional asymmetry is frequently observed in pathways, such as those involved in more than one biological process; different mutations of the same gene or in different genes of the same pathway could impair one or the other function of that pathway triggering the onset of distinct pathological features. Nucleotide excision repair is a conserved DNA repair pathway that cells employ to recognize and remove helix-distorting DNA lesions (Kamileri et al.; Trends Genet. 2012; 11:566-73). Defects in NER represent some of the best-known examples of functional asymmetry; the clinical outcome of NER patients is exceptionally diverse ranging from increased skin cancer predisposition (as in Xeroderma Pigmentosum) to a wide range of progeroid features (as in Cockayne syndrome or trichothiodystrophy) that once present, they manifest in some, but not all, organs. Recent work from our lab allowed us to gain further insights on how random DNA damage events could trigger the onset of tissue-specific pathological features in NER progeroid syndromes (Karakasilioti I et al. Cell metabolism. 2013; 18:3:403-415). Using mice that lack the NER structure-specific endonuclease ERCC1 systemically or specifically in the adipose tissue, we found that the animals exhibited Editorial marked white and brown adipose tissue abnormalities. These appeared to be degenerative changes as both adipose tissue depots developed normally with defects gradually appearing only at later stages in murine life. Further work revealed that the accumulation of irreparable DNA inter-strand crosslinks triggers the transcriptional derepression of pro-inflammatory cytokines in adipocytes, the recruitment of macrophages to sites …