Oxidation and Cell Biology of Aging

What is aging (senescence)

the progressive changes that occur with increasing age that eventually lead to declining cellular and organismal function

What neurological changes occur with aging

abnormal compensatory mechanisms can predispose individuals to neurodegeneration and dementia with cerebral atrophy occuring

what happens to the brain structurally with aging

overall cerebral atrophy can occur

What happens to intestinal smooth muscle with aging

it weakens

what disease/problems can result from weakened intestinal smooth muscle

diverticular disease

bowel obstruction

constipiation

What happens to the number of functional glomeruli in the kidneys with aging

the number decreases

what happens to the glomerular/renal vascular sclerosis with aging

sclerotic changes become more prevalent

What happens to GFR with advanced age

GFR normally decreases

Why does decreased GFR make older adults more vulnerable to kidney disease

they have fewer functional glomeruli and therefore less renal reserve

How does aging affect the threshold for cardiovascular disease

aging lowers the threshold for development of cardiovascular disease

why does aging increase cardiovascular risk

protective and compensatory mechanisms decline

What happens to blood vessels with aging

vascular stiffening occurs

what happens to left ventricular wall thickness

it can increase

what happens to myocardial tissue with aging

myocardial fibrosis can increase

what happens to cardiac valves with aging

calciification of valves and related structures can occur

What happens to aerobic tolerance with aging

it decreases

what happens to cardiomyocytes with aging

problematic cardiomyocyte remodeling can increase

what is the major structural change in the respiratory system with aging

loss of elasticity

what happens to chest wall compliance with aging

it decreases

what happens to the work of breathing with aging

it increases

what happens to residual volume with aging

it increases

what happens to functional residual capacity with aging

it increases

what happens to respiratory capacity with aging

it increases

what happens to respiratory muscle strength and function

they decrease

why are older patients more vulnerable to acute respiratory illness

their respiratory system has less reserve for compensating during acute illness or respiratory failue

What happens to thyroxine and triiodothyronine secretion with aging

they decrease

what is the consequence of decreased thyroid hormone secretion

overall metabolic activity decreases

what happens to circadian rhythms with aging

they become altered

what happens to REM sleep

patients become prone to reduced REM sleep

what happens to glucose metabolism with aging

alterations develop, including changes in insulin secretion

what disease can alter glucose metabolism promote in older adults

diabetes mellitus

what risks increase around menopause

CV disease

loss of bone mass

atrophy of estrogen-responsive tissue

What is healthspan

the period of life spent in relatively healthy functional condition

What is the DNA damage theory of aging

aging results in part from accumulation of damage to nuclear and mitochondrial DNA, producing cellular dysfunction and tissue pathology

What are some examples of exogenous sources of DNA damage

UV radiation

chemicals

X rays

chemotherapies

What are examples of endogenous sources of DNA damage

reactive oxygen species (ROS)

advanced glycogen end products (AGE)

aldehydes

What are ROS

reactive oxygen species that can chemically damage cellular molecules, including DNA

What are AGEs

advanced glycation end products

what can happen to telomeres as a consequence of DNA damage

they can become dysfunctional

What cellular consequences can result from accumulated DNA damage

cell death

senescence

stem-cell loss

polyploidization

What tissue-level consequences can result from DNA damage

cell functional decline and tissue atrophy

What happens to telomeres as cells divide

they progressively shorten

What happens when telomeres become critically short or dysfunctional

cell division stops and cellular senescence can occur

what is cellular senescence

a state in which a cell stops dividing but remains metabolically active

How can ROS affect telomeres

ROS can damage telomere sequences, promoting telomere shortening and dysfunction

What cellular response foes telomere dysfunction activate

DNA damage response (DDR)

What happens to p53 and p21 during the response to dysfunctional telomeres

their expression increases → contributing to cell-cycle inhibition and senescence

What is the basic pathway from telomere dysfunction to senescence

telomere shortening/damage → DNA damage response → increased p53/p21 → cell-cycle inhibition → cellular senescence

What do senescent cells secrete

SASP - senescence-associated secretory phenotype factors

What can SASP do to the extracellular enviroment

alter extracellular matric composition and influence neighboring cells

what immune cells can SASP recruit

T cells

macrophages

How can senescent cells promote systemic inflammation

their SASP can recruit immune cells and alter neighboring tissues, spreading an aging-associated inflammatory phenotype

What is the mitochondrial dysfunction theory of aging

aging is associated with mitochondrial damage and dysfunction that disrupt energy metabolism and produce downstream cellular and tissue abnormalities

what can accumulate in mitochondria duringWh aging

mitochondrial DNA mutations

What is mtROS

reactive oxygen species produced by mitochondria

how can mtROS contribute to aging

they can contribute to oxidative damage and mitochondrial dysfunction

what happens to oxidative stress with mitochondrial dysfunction

oxidative stress increases

what happens to energy metabolism

it can become unbalanced

What happens to oxidative phosphorylation (OXPHOS) during mitochondrial dysfunction

OXPHOS can become impaired

What happens to mitochondrial proteins

damaged proteins can accumulate

what is proteotoxicity

cellular damage caused by accumulation or dysfunction of abnormal/damaged proteins

what types of metabolites can become dysregulated during mitochondrial dysfunction

TCA-cycle intermediates and NAD related metabolites

What are the major downstream consequences of mitochondrial dysfunction

proinflammatory responses

senescence

apoptosis

organismal decline

are-related disease

What can mitochondria release that contribute to inflammation

damaged/toxic mitochondrial materials and DAMPs

What are DAMPs

damage-associated molecular proteins

Why is mitochondrial dysfunction described as having “pleiotropic effects”

because mitochondrial dysfunction can effect many different cellular processes and pathways

What happens to NAD metabolism during aging

NAD+ metabolism becomes altered and NAD+ availability is associated with aging-related cellular dysfunction

What are the 3 NAD+ biosynthetic pathways

1. Kynurenine pathway

2. Preiss-Handler pathway

3. Salvage pathway

What amino acid feeds into the kynurenine pathway

tryptophan

What precursor is associated with the Preiss-Handler pathway

nicotinic acid

what molecule is recycled through the NAD+ salvage pwathway

Nicotinamide (NAM)

Why is NAD+ important to cellular function

It participates in important metabolic and enzyme-mediated processes

What can genomic instability do to NAD+

It can increase consumption of NAD+ by enzymes involved in cellular responses

What age-associated processes are linked to altered NAD+ metabolism

inflammation

neurodegeneration

metabolic decline

mitochondrial dysfunction

ROS accumulation

loss of proteostasis

genomic instability

senescence

apoptosis

cancers

What does loss of proteostasis mean

loss of the cells ability to maintain properly folded, functional proteins

What categories of genes can affect aging

stress resistance genes

inflammation related genes

genes affecting basic metabolism (IGF -relates pathways)

genes involved in overall genetic stability

What is progeria

a condition characterized by features of accelerated/segmental aging

What are the 2 forms of human progeria

Werner syndrome

hutchinson-gilford syndrome

What is werner syndrome

an adult-onset form of progeria

What type of protein is mutated in werner syndrome

DNA helicase involved in DNA repair/unwinding

What type of syndrome is werner syndrome

chromosome instability syndrome

what happens to DNA repair in Werner syndrome

DNA repair is impaired

What happens to cancer risk in werner syndrome

cancer risk is increased

What is the inheritance pattern of werner syndrome

autosomal recessive

What is hutchinson-gilford syndrome

juvenile onset progeria

does hutchinson-guilford syndrome involve the same abnormality as werner syndrome

NO!

lecture specifically states there is no helicase abnormality

what happens to telomeres in hutchinson-guilford syndrome

they are shorted than normal

whap happens to cells in hutchinson-guilford syndrome

they undergo early cellular senescence

What does progeria illustrate about normal aging

disruption of mechanisms involved in DNA maintenance and cellular senescence can produce accelerated/segmental aging phenotypes

Is caloric restriction a method of healthy aging

yes

What happens to body temp with caloric restriction

it decreases

what happens to plasma insulin with caloric restriction

it decreases

what happens to gene expression with caloric restriction

gene expression becomes more stable which is presented as a sign of delayed senescence

Why is sleep important for healthy aging

sleep contributes to recovery and improvement of physiological systems → metabolism, endocrine function, immune responses, brain metabolism

what can poor sleep do to aging

accelerates aging and increases incidence of age related diseases

What age related conditions are associated with poor sleep

cognitive decline

alzheimers disease

hematopoietic stem-cell dysfunction

coronary heart disease

what circulating factor is associated with better sleep quality and quantity

Klotho (S-Klotho)

What does Klotho do

senescence suppressor associated with promoting longevity

What major intervention is presented as beneficial for healthy aging besides caloric reduction

regular exercise

What types of signaling pathways are activated by exercise in skeletal muscles

AMPK

AKT

mTOR

sirtuins

PGC-1 alpha

related signaling molecules