《线粒体生物学与医学》课程教学课件（Mitochondria Biology and Medicine）6 线粒体生物医学 Mitochondrial Free Radical Theory of Aging

Mitochondrial Free Radical Theory of AgingJiangangLong,PH.DInstitute ofMitochondrialBiology andMedicineSchool of LifeScienceand TechnologyXi'anJiaotongUniversity

Mitochondrial Free Radical Theory of Aging Jiangang Long, PH.D. Institute of Mitochondrial Biology and Medicine School of Life Science and Technology Xi’an Jiaotong University

Free Radical Theory of AgingKey points of the TheoryFree radicalsMt ROS and cellular defense systemEvidence supporting Mt aging theoryLeading edge of the Theory

Free Radical Theory of Aging ⚫ Key points of the Theory ⚫ Free radicals ⚫ Mt ROS and cellular defense system ⚫ Evidence supporting Mt aging theory ⚫ Leading edge of the Theory

Overview of agingtheoriesThere are a host of mechanistic theories, onereviewcounted200+Typically researchers studying one aspect ofaging would focus on an underlying aspect thatseemed responsible for aging in that tissue.and then theorize that this process isresponsible for other aspects of aging.Most theories were soon discarded--theydidn't have much explanatory power

• There are a host of mechanistic theories, one review counted 200+. • Typically researchers studying one aspect of aging would focus on an underlying aspect that seemed responsible for aging in that tissue, and then theorize that this process is responsible for other aspects of aging. • Most theories were soon discarded-they didn’t have much explanatory power. Overview of aging theories

程序化衰老理论和损伤衰老理论Procedural Aging Theory and Damage Aging TheoryThe programmed aging theory emphasizes the intrinsic gene-regulated biological clock.101）程序化长寿（ProgrammedLongevity）102）内分泌理论（EndocrineTheory）103）免疫理论（ImmunologicalTheory）。Damagetheoryfocusesonthedamagetoorganismscausedby external environment.101）损耗学说（Wearandteartheory）102)生命速率理论（Rateof livingtheory）103）交联理论（Cross-linkingtheory）104）自由基和线粒体理论（FreeradicalsandMitochondrialtheory105）体细胞DNA损伤理论（SomaticDNAdamagetheory）

程序化衰老理论和损伤衰老理论 Procedural Aging Theory and Damage Aging Theory ⚫ The programmed aging theory emphasizes the intrinsic gene￾regulated biological clock.  1) 程序化长寿（Programmed Longevity）  2) 内分泌理论（Endocrine Theory）  3) 免疫理论（Immunological Theory）。 ⚫ Damage theory focuses on the damage to organisms caused by external environment.  1) 损耗学说（Wear and tear theory）  2)生命速率 理论（Rate of living theory）  3) 交联理论（Cross-linking theory）  4) 自由基和线粒体理论（Free radicals and Mitochondrial theory）  5) 体细胞DNA损伤理论（Somatic DNA damage theory）

OverviewofAgingTheoriesTelomere Theory/ Telomeres (structures at the ends of chromosomes).Shorten with each successive cell division. ShortenedtertherCissuescello notpplestSVDr.ElizabethBlackburnTelomere (in yellow)

⚫ Telomere Theory ✓Telomeres (structures at the ends of chromosomes). ✓Shorten with each successive cell division. Shortened telomeres activate a mechanism that prevents further cell multiplication. ✓This may be an important mechanism of ageing in tissues like bone marrow and the arterial lining where active cell division is necessary. ✓Importantly though, mice lacking telomerase do not show a dramatically reduced lifespan, as the simplest version of this theory would predict. Overview of Aging Theories Dr.Elizabeth Blackburn Telomere (in yellow)

Overview of Aging TheoriesAccumulative-Waste TheoryThe biological theory of ageing that points to a buildup of cells ofwasteproductsthatpresumablyinterfereswithmetabolismDNA damage and DNA repairLoss of repair efficiency with age leads to somatic mutation withdeleteriouseffects.Mitochondrial free radical theoryDamage to mitochondria and cellular proteins from free radicalsgenerated in mitochondria causes cell agingWear-and-TearTheory（磨损学说）The very general idea that changes associated with ageing arethe result of chance damagethat accumulates overtime

• Accumulative-Waste Theory The biological theory of ageing that points to a buildup of cells of waste products that presumably interferes with metabolism. • DNA damage and DNA repair Loss of repair efficiency with age leads to somatic mutation with deleterious effects. • Mitochondrial free radical theory Damage to mitochondria and cellular proteins from free radicals generated in mitochondria causes cell aging. • Wear-and-Tear Theory (磨损学说） The very general idea that changes associated with ageing are the result of chance damage that accumulates over time. . Overview of Aging Theories

Mitochondrial freeradical theory of aging-Harman DAging.chemistryHARMAJGerontPMID:11RelatedThe bidHarmarble.JAmGePMID:50RelatedHarman's93idbirthdayDatePublished:TuesdayFebruary1720o9

Mitochondrial free radical theory of aging-Harman D Harman’s 93id birthday. Date Published: Tuesday, February 17, 2009

Key points of Harman's theory* The common aging process is the initiation offree radical reactions,owing to theirinnateability to producerandom change due to thehighchemical reactivity of the intermediatefree radicals.*Theorywasextended in1972withthesuggestion that most free radicals wereinitiated by the mitochondria at an increasingrate with age,and the life span is determinedbytherateoffreeradicaldamagetothemitochondria

Key points of Harman’s theory The common aging process is the initiation of free radical reactions, owing to their innate ability to produce random change due to the high chemical reactivity of the intermediate free radicals. Theory was extended in 1972 with the suggestion that most free radicals were initiated by the mitochondria at an increasing rate with age, and the life span is determined by the rate of free radical damage to the mitochondria

Free radicals· Free radical:odd number ofelectrons.Chemicalswctron are highlyther molecules.reactive, reaIl are wellMostchemiccontrolled--reing conditions orenzymes. Bd can react withthermodynarmost moleocovalentbondsMoses Gomberg (1866-1947), thefather of radical chemistry

• Free radical: a chemical with an odd number of electrons. • Chemicals with an unpaired electron are highly reactive, readily combine with other molecules. • Most chemical reactions in a cell are well controlled-require specific starting conditions or enzymes. But free radicals are thermodynamically unstable and can react with most molecules and break most covalent bonds. Free radicals Moses Gomberg (1866-1947), the father of radical chemistry

Freeradicals. Normal bond:‘:'represents a pair of electionsBreakingabond:A:B->A:+B+Productsareions.Freeradicalformation:A:B->A-+BProducts each have an unpaired electron!Free radical breakdown of H,O:H:O:H->-OH+HForms Hydroxyl radical and hydrogen radical

• Normal bond: ‘:’ represents a pair of elections Breaking a bond: A:B -> A:- + B+ Products are ions. • Free radical formation: A:B -> A· + B· Products each have an unpaired electron! Free radical breakdown of H2O: H:O:H -> ·OH + H· Forms Hydroxyl radical and hydrogen radical. Free radicals