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Grace B. Athas, Ph.D.LSUHSC CLPC talksNew Orleans LA, May 20, 2017
Recognize premature aging syndromes and genetic/molecular findings
Recognize genes/syndromes with increased healthspan
Identify biological processes associated with aging including:
Mitochondria and metabolic factors
Epigenetics
Telomeres
Recognize “treatments” for aging
Aging –time dependent physiological decline affecting almost all organisms
Senescence –when normal cells cease to divide
Life expectancy ‐ statistical measure of the average time an organism is expected to live
Life span –maximum life observed in a group
Health span ‐length of time you are truly healthy and thriving during your life span
Centenarians –live to or beyond 100
Oxidative stress – free radicals damage cells
Genetic Mutation – accumulation of mutations cause aging
Inaccurate repair of DNA damage
Mitochondrial Dysfunction
Metabolic dysfunction
Cross‐linking of proteins
Telomere length
Neuroendocrine –changes in hormone regulation
Decreased immune function
Slowing metabolism
Increased risk of Chronic disease –hypertension, atherosclerosis, diabetes, kidney disease, cancer
Eye trouble
Hearing loss
Decrease in muscle strength and stamina Sarcopenia
Memory loss
Skin and hair changes
Bone loss – Height, weight bearing
Sleep changes
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Hundreds of rare syndromes
Most autosomal recessive
Premature aging and death
Genes implicated – interruptions in DNA repair (most)
Progeria: Hutchinson ‐ Gilford Progeria Syndrome (HGPS)
Called “Benjamin Button Disease” by lay public and news agencies (2008)
Spontaneous mutation – 1824C > T, in LMNA gene ‐generally NOT inherited but would be Autosomal Dominant
Children develop symptoms in first few months – first year of life
Failure to thrive
Thin beaked nose, small chin
Skin hardening condition
Worsens ~ age 12
Accelerated atherosclerosis
Mid teens life span
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No cancer or diabetes
Accelerated Atherosclerosis
Die early
DNA Repair problems
“Adult Progeria”
Autosomal Recessive
WRN gene on Chromosome 8 – DNA helicase
Symptoms appear after puberty – 20’s Short stature
Teenagers do not have growth spurt
Six Cardinal signs:
Premature greying of hair or hair loss
Bilateral cataracts
Atrophied or tight skin
Soft tissue calcification
Sharp facial features
Abnormal high pitched voice
Live to 50 –die of heart disease or cancer
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Age 36
Rare, Autosomal recessive
Growth failure, photosensitivity, progressive pigmentary retinopathy, birdlike facies
Calcifications in the brain, demyelination of nerves & premature aging
Two main typesType I –features appear in first decade of life –death by 2nd decade of life
Type II –presents at birth –live 6 or 7 years
Cellular sensitivity to ultraviolet (UV) irradiation
Mutations of genes critical for nucleotide‐excision repair and RNA transcription
NOT associated with skin cancer
CSA/ERCC8 and CSB/ERCC6
Chromosome 5 and 10
Rare, autosomal recessive
~ 8 chromosomes
Unable to repair UV light induced DNA damage
Multiple basal carcinomas
Cause of death ‐Malignant melanoma and squamous cell carcinoma
Neurological abnormalities – poorly understood but NOT due to exposure to UV light
Live to 20‐40
Nucleotide excision repair defect (NER)Global Genome NER (GG‐NER)
Transcription Coupled (TC‐NER)
Seven repair genes ‐ XPA through XPG
XPA and XPC sense DNA damage
XPD and XPB gene products are part of a 9‐subunit protein complex (TFIIH) ‐needed for the open complex formation
XPF and XPG –endonucleases
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Autosomal recessive
Mutations in Growth Hormone Receptor
Short stature; prominent forehead, depressed nasal bridge, underdeveloped mandible
Increased sensitivity to insulin
No cancer or diabetes
Discovered in Israel in the 1950’s; found around Mediterranean
Found in Ecuador in the 1980’s
“Conversos”
or NOGrowthhormone
Pituitary
Increased HEALTHSPAN
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About 300 causes
Achondroplasia – 70%Fibroblast Growth Factor Receptor 3
FGFR3 constitutively active, inhibiting bone growth
Pituitary dwarfism ‐ growth hormone deficiency
All have normal life span
“It's paradoxical that the idea of living a long life appeals to everyone, but the idea of getting old doesn't appeal to anyone.”
Genetics
Epigenetics
MetabolicMitochondria
Reactive oxidative species (ROS)
Other inflammation/protein changes
Telomeres
>1800 genes identified
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>1800 genes
Four Genome‐Wide Association Studies Identify New Extreme Longevity Variants.The Journals of Gerontology: Series A, 2017; DOI: 10.1093/gerona/glx027
Heritable changes that do NOT involve change to the DNA sequence
A change in Phenotype without a change in Genotype
Post transcriptional modifications to the DNA nucleotides or post translational modifications to histone proteins
Addition of methyl group at cytosine residue at CpGdinucleotides
These methyl groups project into the major groove of DNAand inhibit transcription
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The set of nucleic acid methylation modifications in an organism’s genome or in a particular cell type
Normally,Global hypomethylation of repetitive regions
Site specific hypermethylation at certain promoters –turn on gene expression
In Aging,Repetitive regions become methylated –leads to genomic instability
Certain promoters now lose methylation –turn off
Profound change in chromosomal architecture, genomic integrity, and gene expression patterns
Reduction in histone proteins; changes in histone proteins
Changes in methylation patterns
Latest epigenetic discoveries
Small RNA molecules ‐ inhibit gene expression & translation by binding to mRNA molecules through base pair complementarity
MicroRNAs and their roles in agingThalyana Smith‐Vikos, Frank J. SlackJ Cell Sci 2012 125: 7‐17; doi: 10.1242/jcs.099200
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Circular genome – 13 coding genes
Each time the mtDNA replicates, there is amutational riskIn the aged human, virtually every mitochondrial
genome has a mutation
Cells can tolerate a high proportion of mutantmitochondrial genomes, but once a threshold is passed energy production falls dramatically
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2015 Nat Med 21: 1416‐14232015 Nat Med 21: 1416‐1423
Macrolide antibiotic from Streptomyces hygroscopicus
Immunosuppressive and antiproliferativeproperties
Inhibits mTOR
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Silent information regulator genes
Adenosine monophosphate‐activated protein kinase (AMPK)
Physiological Effects of AMPKSchematic of selected physiological effects on AMPK and the intermediate mediators. Arrows signify activation, T bars signify suppression. Green signifies prolongevity, red signifies antilongevity.
AutophagyThe natural, regulated, destructive mechanism of the cell that disassembles unnecessary or dysfunctional components and recycles them
Inhibition of autophagy –aging
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Lipofuscin –wear and tear or aging pigment, yellow –brown, seen in aging persons
Lipid peroxidation of membranes and covalent protein modification by ROS
Accumulates in dying cells and cells undergoing authophagy
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Dyskeratosis Congenita
Nature 464 2010; doi:10.1038/nature08982
DyskeratosisCongenita
Cancer
Fasting and Calorie Restriction
Calorie restriction mimetics
Other Medications
Exercise
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Abstinence from food
Physiologic response to fasting:Post absorptive phase –glycogen used as main energy source
When glycogen depleted, amino acids serve as source for gluconeogenesis
Glycerol and fatty acids released from adipose become major source of energy. Fat derived ketone bodies become the major energy source
Fat reserves become exhausted, muscle degradation occurs to fuel gluoconeogeneis
70 kg person (154 lbs)‐ 2‐3 months of caloric requirements from fat reserves
5 days a month fast; rest of the time ad libitum
Weekly 2 day fast, 5 day NL
Reduces mTOR, IGF‐1, & PKA pathways
Reduction in calories without malnutrition
30% reduction in calories/day
Prolongs life span in in dogs, rodents, worms, flies, yeasts, & prokaryotes
In eukaryotes –conserved nutrient pathways involved
Induces stress related transcription factors
2015 Nat Med 21: 1416‐1423
National Geographic Magazine
Identified 5 regions in the world where people lived longest:
Okinawa, Japan
Sardinia, Italy
Nicoya, Costa Rica
Icaria, Greece
Loma Linda, CA (7th Day Adventists)
Previous demographic work counting centenarians (circled areas of the map with blue pen) –the blue zone
Longest life expectancy in the worldLongest health expectancy, healthy youthful looking, energetic Low rate of heart disease, stroke, cancer even stomach cancer, osteoporosis, Alzheimer’s“Okinawa inhabitants reach ages similar to the Japanese average of 86 for women and 78 for men. However, the real encouraging factor is not that people reach these ages, but they grow old in a much better state. Some in their 90's can honestly vouch that they still have an active sex life.”
Fries JF. New England Journal of Medicine 1980;303:131‐5)
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Low‐calorie, low glycemic diet. Consume only 25% the amount of sugar and 75% the amount of fat than what the Japanese eat. Diet consists of vegetarian, seafood and soy. No meat, eggs or dairy products
Anti‐oxidant rich foods: they consume about 300 g of green, yellow, orange vegetables, fruits, tubers a day. These vegetables are rich in vitamin C, A and flavonoids
Calorie control: hara hachi bu, a cultural habit consisting of only eating until they are 80% full and staying physically active the natural way. Average body mass index (BMI) of 18 to 22”.
Okinawa centenarian study. Fries JF. New England Journal of Medicine 1980;303:131‐5.
Geographic and Ideological Isolation: Centenarians live in isolated areas, on an island, peninsula or in religious isolation such as the 7th
Adventists with little contact with the modern world. They operate as a community and take care of each others needsThey live outdoors a good part of the time and get plenty of sun exposure They get plenty of physical activity: working in the fields, walking or bicycling to neighbor locationsThey have a strong sense of belonging, perpetrate tradition, family celebrationsHappy and sense of purpose
Calorie Restriction mimetics
Influence metabolic functions
Very popular
Studies disappointing
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Upregulates AMPK
DOI 10.1002/emmm.201000080| Published online 01.07.2010EMBO Molecular Medicine (2010) 2, 247‐257
Telomerase activator
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Loss of muscle mass, quality and strength that occurs with aging
Rate of 1% loss per year after the age of 50
Resistance Weight trainingAdequate NutritionSupplements
Larry A. Tucker. Physical activity and telomere length in U.S. men and women: An NHANES investigation. Preventive Medicine, 2017; 100: 145 DOI: 10.1016/j.ypmed.2017.04.027
High levels of exercise linked to nine years of less aging at the cellular level
•Intrinsic (chronologic) aging occurs throughout the skin and causes primarily functional losses.•Caused by oxidative damage, cell senescence, amino acid racemization, nonenzymatic glycosylation of proteins.•Displays flattening of the dermal–epidermal junction, decreased cellularity, decreased dermal thickness, loss of vascular and lymphatic beds.•Photoaging is the superposition of chronic ultraviolet-induced damage on intrinsic aging and accounts for most age-associated changes in skin appearance.•Triggered by receptor signaling, mitochondrial damage, and protein oxidation.•Displays variable epidermal thickness, dermal elastosis, decreased/fragmented collagen, increased matrix degrading metalloproteinases, inflammatory infiltrate, and vessel ectasia.•Dermatologic problems with increased incidence in the elderly include skin cancer, xerosis, pruritus, varicella-zoster infection, ulcers, bullous pemphigoid, and drug eruptions.
Smoking
Degree of natural skin pigmentation (less pigmentation, more wrinkles)
Sun and ultraviolet exposure
Heredity (some families wrinkle more)
The loss of subcutaneous fat on a person's body (people with more subcutaneous fat have fewer wrinkles)
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https://www.slideshare.net/drnateghi/skin‐aging‐28801041
Vitamin A acid ‐tretinoin [Retin A, Renova]
Alpha‐hydroxy acids
Antioxidants
Ordinary moisturizers
Glycolic acid peels
Deeper peels
Micordermabrasion and Dermabrasion
Laser resurfacing
Non ablative laser resurfacing
Plastic surgical procedures
Botox
Fillers
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Front. Microbiol., 19 August 2016 | https://doi.org/10.3389/fmicb.2016.01204
www.bluezones.com
progeriafamilycircle.blogspot.com
Progeria Research Foundation
Fries JF. 1980 Aging, natural death, and the compression of morbidity. NEJM 303:131‐5Hands, SL. Et al. 2009 mTOR’s role in ageing: protein synthesis or autophagy? Aging Vol 1 No. 7: 586‐577
Lopez‐Otin, C. et al. 2013. The Hallmarks of Aging. Cell 153:1194‐1217
Johnson, SE. et al. 2013 mTOR is a key modulator of ageing and age‐related disease. Nature 493:338‐345
Giblen, W. et al. 2014 Sirtuins: guardians of mammalian healthspan. Trends Gen 30, No 7: 271‐285
deCabo, R. et al. 2014. The search for anti‐aging interventions: from elixersto fasting regimens. Cell 157: 1515‐1526
deCavanaugh EMV. et al. Angiotensin II blockade: how its molecular targets may signal mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. 2015. Am J Physiol. 309: H15‐H44
Finkel T. The metabolic regulation of aging. 2015 Nat Med 21: 1416‐1423