Senescence Depletion of stem/ of mature cells progenitor cells
Fig. 2.28 Theroleoftelomeresandtelomeraseinreplicativesenescenceofcells.(A)Mechanismsandconsequencesoftelomereattrition.Repeatedcelldivisionassociatedwithagingleadstoprogressiveshorteningoftelomeres,whichtriggerssenescenceandlossofstemcellpools.(B)Telomereattritionischaracteristicofsomaticcells.Stemcellsmaintaintheirtelomeresandare,therefore,capableofmorecyclesofreplication.Cancercellsfrequentlyactivatetelomeraseandarethusabletomaintaintelomeres.
http://ebooksmedicine.net 56CHAPTER 2CellInjury,CellDeath,andAdaptations (the search for the “elixir of youth”) but also because elucidating these pathways might tell us about the mechanisms that cause aging. Calorie restriction has been found to slow down aging and prolong life in every species tested from flies to mice. It is now thought that calorie restriction alters signaling pathways that influence aging (
Fig. 2.27 ). Among the biochemical alterations associated with calorie restriction that have been described as playing a role in counteracting the aging process is reduced activation of insulin-like growth factor receptor signaling, which involves a downstream network of kinases and transcription factors. Reduced IGF-1 signaling leads to lower rates of cell growth and metabolism and possibly reduced errors in DNA replication, better DNA repair and improve protein homeostasis. Calorie restriction also serves to improve immunity. All of these inhibit aging.
• Persistent inflammation. As individuals age, the accumulation of damaged cells, lipids, and other endogenous substances may activate the inflammasome pathway (Chapter 5), resulting in persistent low-level inflammation. Inflammation in turn induces chronic diseases, such as atherosclerosis and type 2 diabetes. Cytokines produced during inflammatory reactions may themselves induce cellular alterations that exacerbate aging, and chronic metabolic disorders may accelerate the aging process.
Clinical observations and epidemiologic studies have shown that physical activity and, as mentioned previously, calorie restriction slow the aging process, whereas stresses, perhaps acting via increased production of glucocorticoids, accelerate aging. Alas, the precise mechanisms underlying these effects remain to be defined, and for now we all remain vulnerable to the ravages of age.
Resultsfromacombinationofmultiple,progressivecellularalterations,including:
Replicativesenescence:reducedcapacityofcellstodividesecondarytoprogressiveshorteningofchromosomalends(telomeres)
Defectiveproteinhomeostasis:lossofnormalproteinsandaccumulationofmisfoldedproteins
Agingisexacerbatedbychronicdiseases,especiallythoseassociatedwithprolongedinflammation,andbystress,andissloweddownbycalorierestrictionandexercise.
It should be apparent that the various forms of cellular derangements and adaptations described in this chapter cover a wide spectrum, ranging from reversible and irreversible forms of acute cell injury, to adaptations in cell size, growth, and function, to largely unavoidable consequences of aging. Reference is made to these many different alterations throughout this book, because all instances of organ injury and ultimately all cases of clinical disease arise from derangements in cell structure and function.
Calado RT, Young NS: Telomere diseases, N Engl J Med 361:2353, 2009. [An excellent review of the basic biology of telomeres, and how their abnormalities may contribute to cancer, aging, and other diseases.]
Chipuk JE, Moldoveanu T, Llambl F, et al: The BCL-2 family reunion, Mol Cell 37:299, 2010. [A review of the biochemistry and biology of the BCL-2 family of apoptosis-regulating proteins.]