The pathology of aging: J Path special issue

The Journal of Pathology‘s most recent issue is devoted entirely to the pathology of aging. From the introductory article by Martin and Sheaff:

The rising numbers and proportion of aged individuals in the population is a global demographic trend. The diseases associated with ageing are becoming more prevalent, and the associated healthcare costs are having a significant economic impact in all countries. With these changes have come great advances in our understanding of the mechanisms of ageing. The mechanisms of cellular ageing at a genetic, protein and organelle level are becoming clearer, as are some of the more complex associations between environment and ageing. System ageing is also becoming better understood, and the potential biological advantages of ageing are being explored. Many of the advances in these fields are opening up the prospect of targeted therapeutic intervention for ageing and age related disease.

The articles cut a broad swath through the field, from molecular changes in aging cells to tissue- and system-scale phenomena in immunology, reproductive endocrinology, and beyond. The authors are in many cases the same eminences grises who would have written comparable reviews in high-impact basic science journals.

J Path itself is the highest-impact journal devoted to pathology, and its readership consist primarily of MDs and academic pathology researchers. The devotion of an entire issue to this subject is just the latest example of the increasing mainstream attention being paid to the biology of aging.

For your delectation, the table of contents:

• The pathology of ageing: concepts and mechanisms
  JE Martin, MT Sheaff

• Hallmarks of telomeres in ageing research
  JW Shay, WE Wright

• p53: at the crossroad between cancer and ageing
  C Papazoglu, AA Mills

• Autophagy, organelles and ageing
  A Terman, B Gustafsson, UT Brunk

• Immunosenescence of ageing
  AL Gruver, LL Hudson, GD Sempowski

• Ageing of the conduit arteries
  SE Greenwald

• The endocrine system and ageing
  HS Chahal, WM Drake

• Ageing and the brain
  MM Esiri

• Ageing and hearing loss
  XZ Liu, D Yan

• Renal ageing
  JE Martin, MT Sheaff

• The ageing male reproductive tract
  N Sampson, G Untergasser, E Plas, P Berger

• Reproductive ageing in women
  O Djahanbakhch, M Ezzati, A Zosmer

• The aged breast
  RA Walker, CV Martin

• Skin ageing and its treatment (p 241-251)
  L Baumann

• Morphology, mechanisms and pathology of musculoskeletal ageing
  AJ Freemont, JA Hoyland

While J Path doesn’t have a newsstand price, I must say I’d be tempted to pay it for this issue.

 

I can’t hear you, there’s superoxide in my ear

An emerging story in the literature of age-related decline is the role of mitochondrial dysfunction and oxidative damage in the inner ear, resulting in hearing loss. E.g. this recent article from Jiang et al., who describe the tissue-specific changes in oxidative stress markers throughout the aging ear:

The mammalian inner ear loses its sensory cells with advancing age, accompanied by a functional decrease in balance and hearing. This study investigates oxidant stress in the cochlea of aging male CBA/J mice. Glutathione-conjugated proteins, markers of H₂O₂-mediated oxidation, began to increase at 12 months of age; 4-hydroxynonenal and 3-nitrotyrosine, products of hydroxyl radical and peroxynitrite action, respectively, were elevated by 18 months. … Conversely, antioxidant proteins (AIF) and enzymes (SOD2) decreased by 18 months in the organ of Corti (including the sensory cells) and spiral ganglion cells but not in the stria vascularis. These results suggest the presence of different reactive oxygen species and differential time courses of oxidative changes in individual tissues of the aging cochlea. An imbalance of redox status may be a component of age-related hearing loss.

One obvious potential treatment for oxidative damage is supplementation with anti-oxidant compounds, of which we have dozens in the cupboard — so why not give them a try? When you’ve got a nice hammer, after all, everything looks like a nail. Unfortunately, early efforts in this direction have met with limited success. From Davis et al.:

A compound capable of preventing age-related hearing loss would be very useful in an aging population. N-acetyl-l-cysteine (l-NAC) has been shown to be protective against noise exposure, a condition that leads to increased oxidative stress. … Our hypothesis is that AHL defect results in increased sensitivity to oxidative stress and l-NAC would be able to protect the hearing of a mouse model of pre-mature AHL, the C57BL/6J (B6) mouse strain. l-NAC was added to the regular water bottle of B6 mice (experimental group) and available ad lib. The other group received normal tap water. Hearing was tested monthly by the ability to generate the auditory brainstem response (ABR). … There was no difference in ABR thresholds or in histopathology between the control group and the group receiving l-NAC in their drinking water. In contrast to the protective effects of l-NAC against noise-induced hearing loss, the lack of protective effect in this study may be due to (i) the dosage level; (ii) the duration of treatment; (iii) the biochemical mechanisms underlying age-induced hearing loss; or (iv) how the mouse metabolizes l-NAC.

It’s a negative result, and as the authors themselves are quick to point out, such results come with a host of qualifications. To their list (at the end of the abstract) I would add that not every antioxidant is equally available to every subcellular component in every tissue (more discussion about this in yesterday’s post), and that NAC might be the wrong choice for the inner ear; then again, NAC has been shown to be protective against acute noise exposure, so it’s likely that the compound at least makes it into the cochlea.

I mention this not to discourage future work on antioxidants in age-related hearing loss, but rather to underscore the challenges in design and interpretation of what might seem to be simple experiments, and to remind us that we can’t necessarily draw final conclusions on the basis of negative results. Dosage, pharmacokinetics, genetic idiosyncrasies of animal models, and timing all play a role in the efficiacy of any pharmacological treatment; the first conditions tested might not succeed. Exploring the full range of possible regimens is combinatorially complex, and time-consuming; patience is required.

For now, the efficacy of antioxidants in preventing or forestalling age-related hearing loss remains an open question, but one that I’m sure these and other labs will continue hammering away on.