Chapter 1
Aging and Senescence
BASICS
OVERVIEW
While the adage "Age is not a disease" may be true, the process of aging can be considered one of the most important, and potentially modifiable, causes of disease, disability, and death in adult dogs. (McKenzie) A set of complex but comprehensible processes increase with time that result in a progressive loss of function, a decrease in reserves and recovery capacities, that put the individual at risk for disease and even death. Anticipated, "normal" aging processes need to be distinguished from pathological issues ("non-programmed disruptions of aging")1 with attempts for coordinated management.
The chronological age of our patients is a major factor, yet it is the individual's response that can greatly influence biological or physiologic age. The ultimate goal is to minimize the impacts of aging changes to maintain health, resilience, and functional capacity for as long as possible (healthspan). Recently, there has been a growing recognition that geroscience approaches in veterinary medicine can have a much greater impact on health and disease burden than traditional biomedical strategies aimed at treating individual diseases in isolation. (Kaeberlein)
Much of the research on aging and associated issues comes from human medicine and laboratory animal data, but there is a growing field of information concerning dogs and even cats. In fact, there is so much literature in this field that this chapter can only present an abbreviated listing of some of the most pertinent facts. When possible, specific dog and cat data is presented.
Terms Defined
- Aging is the decline and deterioration of functional properties at the cellular, tissue, and organ levels. This loss of functional properties yields a loss of homeostasis and decreased adaptability to internal and external stress yielding an increased vulnerability to disease and mortality. (Fedarko)
- Chronological age-actual "calendar" age of the individual
- Biological (genetic) age-how old your cells and tissues are based on physiological parameters-to provide the predicted longevity.
- Lifespan-actual number of years an individual is alive.
- Healthspan-the time an individual is able to maintain good health with a short period of morbidity before death.
- Geroscience refers to research aimed at understanding the mechanisms of biological aging, defining the genetic, epigenetic, and environmental features that determine the rates of aging.2
- Robustness-the ability to maintain optimal physiological function in the face of external stressors.
- Resilience-the ability to return to baseline following stressor disturbance.
- Frailty-a syndrome characterized by the decrease in physiologic reserves, cognitive performance, and dysregulation of multiple body systems with an increased vulnerability to stressors.
- Functional capacity a direct measure of the ability of cells, tissues, and organ systems to operate properly/optimally and is influenced by both genes and environment.
- Senescence-cellular response that blocks further proliferation and alters the cell's phenotype.
- Immunosenescence-the decline in the function of the adaptive immune system that occurs during aging and is associated with thymic involution, alterations in T cell subsets, and reduction in antibody production.
- Inflammaging-the term used to describe the pro-inflammatory state associated with aging.3
- Apoptosis-cellular response to remove damaged or aberrant cells through controlled cell death with no inflammatory response.
- Oxidative stress (OS)-the imbalance between free radicals and antioxidants in the body that can cause damage and disease.
ISSUES AND OPTIONS
The "Normal" Aging Process
- Mechanisms of cellular maintenance include:
- DNA repair
- synthesis and fidelity surveillance
- detection and clearance of defective proteins and lipids
- clearance of defective organelles and cells
- defense against pathogens and injury
- Main contributors to mammalian aging (Jiminez, Lopez-Otin, Sandor)
- Genomic instability-damaged with age by mutations, chromosome rearrangement, and increase in copy number variants (CNV)
- Hinders cell function resulting in cellular senescence, apoptosis, or even malignancy
- ? Increased apoptosis can lead to atrophy, or decreased removal of accumulation of senescent cells.
- Deficiencies in DNA repair
- Oxidative damage from reactive oxygen species (ROS), free radicals that target DNA, lipids, and protein
- ? Oxidative DNA lesions increase with age and with decreased expression of antioxidant enzymes-neurodegeneration
- Optimal levels of oxidation are needed; they should not be completely irradicated. ROS at low levels are important signaling molecules.
- Transposable element-transponsons increase with age; can be induced by stressors-heavy metal toxins, genotoxic agents, and nutrition.
- Assessing when mitochondrial DNA mutations first appear (especially in larger breed dogs), may be helpful in assessing aging and age-related diseases.4
- Telomere attrition-the protective portions at the ends of chromosomes that shorten with each cell division in somatic cells (not in germ line cells-they have sufficient telomerase)
- Limits the number of cycles (Hayflick limit) and correlates with lifespan.
- May limit the growth of malignant cells but can also contribute to tumorigenesis if chromosomes link end-to-end.
- Telomeres shorten faster under conditions of chronic inflammation and oxidative stress in humans and animals;5 even associated with feline chronic kidney disease.6
- Comprehensive lifestyle changes could stabilize telomeres and decrease oxidative stress.
- Telomeric restriction fragments may vary by dog breed, so this should be considered in evaluation.7, 8
- Epigenetic alterations-mechanisms that modulate gene expression and transcription
- DNA is packed into dense chromatin-heterochromatic or more open euchromatic; their ratio is associated with aging.
- Methylation of cytosines may block transcription
- ? Hyperactive for pro-aging genes but repressing anti-aging genes
- Regulation by various enzymes working on sirtuin genes-longevity impact
- Age-related changes-alter mRNA transcriptome: gero-miRNAs (microRNAs) target other longevity miRNAs.
- Epigenetic regulation may be dog breed specific.9
- Proteostasis disruption of proteome (all protein types in a cell)
- Cell senescence and proteinopathies-accumulation of misfolded proteins
- Aberrant proteins (altered by glycation) can induce inflammation.
- Chaperones and protein quality control facilitate appropriate folding of maturing proteins and protect them; these are reduced with aging.
- ? Heat-shock proteins (Hsp)-upregulation can extend lifespan in mice
- ? Not always protective-can be neurodegenerative
- Ubiquitin-Proteasome (UPS)-performs selective removal of misfolded and senescent proteins-linked to longevity
- Autophagy-targets diseased mitochondria and large protein aggregates, fuses with lysosomes and degrades/recycles components
- ? If impaired-can be a major factor in aging regulation.
- ? Lipofuscin (aging pigment) can accumulate in lysosomes due to oxidation of unsaturated fatty acids. These are insoluble and refractile to cellular removal, compromise organelle function.
- Nutrient-sensing deregulation-nutrients used for cell metabolism, protein synthesis, autophagy
- TOR-target of rapamycin kinase-determines rates of protein turnover and metabolism
- ? Rapamycin-approved immunosuppressant, transplant rejection drug but has severe side effects at medical dosages
- ? Increased lifespan seen with a decrease of mammalian mTOR-smaller dosage without side effects
- ? Main signaling-insulin and IGF1 signaling pathways
- FOXO (forkhead box O)-role in tumor suppression and age-related diseases
- Sirtuins and nicotinamide adenine dinucleotide (NAD)-dependent factors.
- AMPK (5´AMP-actived protein kinase)-detects levels of AMP, counteracts IGF1 by inhibiting TOR and activating FOXO3a-neuroprotective role.
- Therapy potential-metformin and acarbose (anti-diabetic medications)-exert anti-aging effect with mild effects at correct dose in dogs.
- The metabolome (the collection of metabolites in a cell or organism) was analyzed in a caloric restriction study on Labradors to help assess metabolic steps that may impact longevity.10
- Mitochondrial dysfunction-main source of energy; mitochondrial respiration generates ATP but also...
