In cells that do not replicate or are replaced only infrequently, we hypothesize that unrepaired damages accumulate over time and in the end this will undermine the integrity of the cells and the organism.
Aging is inevitable and likely caused by wear and tear through life. Still aging is unequal and impacts individuals to a variable extent, suggesting that genetic makeup and epigenetic regulations exert fundamental roles. In cells that do not replicate or are replaced only infrequently, we hypothesize that unrepaired damages accumulate over time and in the end this will undermine the integrity of the cells and the organism. In the brain we have shown that this process is neither stochastic nor does it affect all neurons to the same extent; instead certain cell types are more impacted by aging than others. In normal aging loss of neurons is small and selective, while the more widespread alterations include loss of synapses and axonal dystrophy.
Among the neuronal populations vulnerable to aging are the monaminergic systems of the brain. These systems modulate a range of the brain’s functional domains such as cognition, motor behavior, mood modulation, exploration-arousal and sleep.
With advancing age cognitive functions decline in humans and rodents alike. Postmenopausal females are at greater risk to develop cognitive deficits and dementia than age-matched males. We intend to resolve if learning difficulties and memory decline evolving during normal aging of isogenic individuals associate with locus-specific differences in epigenetic modulation. To address the variable impact of aging on individuals we assess if epigenetic differences increase with advancing age among individuals in isogenic age-cohorts. In particular, we address the significance of reproductive senescence and ovarian sex steroids in this context.
Skeletal myofibers are composed of postmitotic cells. With advancing age there is an inevitable loss of functional muscle mass (sarcopenia) and using rodent models we hypothesize that myofiber denervation is a key component of sarcopenia. Motoneurons are not lost to any greater extent; instead it is an increasing incapacity to maintain contact with all myofibers of a motor unit. We are currently gathering evidence supporting this notion and in collaboration with Uppsala University and Clinical Physiology, Karolinska Hospital, testing this hypothesis on human sarcopenia.
An important cellular stigmata in both modified/damaged proteins, a third line of our research is to understand aging-induced changes in the cellular machineries handling protein degradation.
Behavioral impairments of the aging rat.
Altun M, Bergman E, Edström E, Johnson H, Ulfhake B
Physiol. Behav. 2007 Dec;92(5):911-23
Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway.
Altun M, Besche HC, Overkleeft HS, Piccirillo R, Edelmann MJ, Kessler BM, et al
J. Biol. Chem. 2010 Dec;285(51):39597-608
Factors contributing to neuromuscular impairment and sarcopenia during aging.
Edström E, Altun M, Bergman E, Johnson H, Kullberg S, Ramírez-León V, et al
Physiol. Behav. 2007 Sep;92(1-2):129-35
Increased glutathione levels in neurochemically identified fibre systems in the aged rat lumbar motor nuclei.
Ramírez-León V, Kullberg S, Hjelle OP, Ottersen OP, Ulfhake B
Eur. J. Neurosci. 1999 Aug;11(8):2935-48