Management of multicellular senescence and oxidative stress

Abstract

Progressively sophisticated understanding of cellular and molecular processes that contribute to age-related physical deterioration is being gained from ongoing research into cancer, chronic inflammatory syndromes and other serious disorders that increase with age. Particularly valuable insight has resulted from characterization of how senescent cells affect the tissues in which they form in ways that decrease an organism's overall viability. Increasingly, the underlying pathophysiology of ageing is recognized as a consequence of oxidative damage. This leads to hyperactivity of cell growth pathways, prominently including mTOR (mammalian target of rapamycin), that contribute to a build-up in cells of toxic aggregates such as progerin (a mutant nuclear cytoskeletal protein), lipofuscin and other cellular debris, triggering formation of senescent cellular phenotypes, which interact destructively with surrounding tissue. Indeed, senescent cell ablation dramatically inhibits physical deterioration in progeroid (age-accelerated) mice. This review explores ways in which oxidative stress creates ageing-associated cellular damage and triggers induction of the cell death/survival programs' apoptosis, necrosis, autophagy and 'necroapoptophagy'. The concept of 'necroapoptophagy' is presented here as a strategy for varying tissue oxidative stress intensity in ways that induce differential activation of death versus survival programs, resulting in enhanced and sustained representation of healthy functional cells. These strategies are discussed in the context of specialized mesenchymal stromal cells with the potential to synergize with telocytes in stabilizing engrafted progenitor cells, thereby extending periods of healthy life. Information and concepts are summarized in a hypothetical approach to suppressing whole-organism senescence, with methods drawn from emerging understandings of ageing, gained from Cnidarians (jellyfish, corals and anemones) that undergo a unique form of cellular regeneration, potentially conferring open-ended lifespans.

Keywords: apoptosis; autophagy; necroptosis; necrosis; oxidative stress; senescence.

Fig. 1. Telomerase and cell division-dependent decrease in telomere length

Chromosome telomere length and structural integrity in eukaryotic cells derived from fetal tissue are initially maintained by high levels of telomerase. Activity of this enzyme progressively decreases with each cycle of cell division, resulting in greatly shortened telomeres, decreased organization of chromatin and deleterious effects on cells, including cell division cycle arrest and cellular senescence (Campisi, [3]; Feng et al., [13]; Jaskelioff et al., [14]).

Fig. 2. Influence of young undamaged versus old or damaged cells on health and disease

Young, undamaged cells express products and perform functions that contribute to healthy homeostasis. Old cells and damaged cells that have developed a senescent phenotype (stress-induced prematurely senescent, SIPS) affect surrounding tissue in ways that contribute to age-associated deterioration, including dysregulated inflammation and cancer (Campisi, [3]; Hara et al., 2011). Source: Aging and Stress Group, University of Namur, Belgium.

Fig. 3. Inhibition of multi-organ deterioration in progeric mice by reactivation of endogenous telomerase expression

Telomerase-deficient mice engineered to contain a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-estrogen receptor (TERT-ER) allele respond to stimulation with 4-OHT by reactivation of telomerase activity and maintenance of telomere length along with healthy function of tissues and organs. Mice not treated with 4-OHT exhibit low telomerase activity and rapid deterioration of multiple cellular and organ functions expected as an outcome of defective telomeres. Conversely, mice implanted with 4-OHT-releasing pellets experienced somatic telomerase reactivation and significant delay of progeric phenotype onset. Dramatic results of these evaluations are shown below. Here, the 4-OHT-treated, telomerase-enhanced 48 week old mouse on the left, exhibits a physical age apparently younger than the 35 week old non-4-OHT-treated progeric animal. From: Aging Ills Reversed in Mice”. Article by Gautam Naik, The Wall Street Journal, November 28, 2010: Press release, Ronald DePinho laboratory, Dana-Farber Cancer Institute in Boston, MA, USA.”. Photograph by Dr. Mariela Jaskelioff, lead investigator.

Fig. 4

Development/age-related shift in tissue representation of functional cell types.