II-28. Molecular and cellular aging

分子・細胞レベルの老化

Definition & Forms of Aging

Progressive deterioration of physical function → declining health + ↑mortality
Exponential ↑ in age-specific mortality. Largest risk factor for chronic disease (heart disease > HTN/smoking/cholesterol/diabetes, also main risk for Alzheimer’s)
↓stress resilience (cellular & molecular) → slower return to equilibrium (e.g. higher infection mortality in the elderly)
Environmental (inflammation, epigenetics, cellular stress) + lifestyle (diet, smoking, exercise) factors amplify aging

Molecular-Level Theories

Genomic instability

DNA alterations from ROS + replication errors → mutations, transposable-element activation, or critically short telomeres
Consequences: mutations → cancer, chronic DNA damage → cell death, and senescence / “inflamm-aging”

Telomere shortening

Replication shortens telomeres → Hayflick limit (~50 divisions). Telomeres are its underlying cause
Telomerase (reverse transcriptase) elongates telomeres — upregulated in cancer to bypass Hayflick. Stem cells have intermittent activity, while somatic cells lack it → replicative senescence
Telomere shortening is likely not the cause of aging, but key in tumor protection

Epigenetic alterations

Chemical DNA/histone modifications → altered gene expression → genome instability/senescence
DNA methylation clocks: CpG-island methylation silences genes, methylation ↑ with age, and Horvath’s clock estimates biological age → rate of aging
SIRT-1 (sirtuin histone deacetylase, first pro-longevity gene): reopens DNA for transcription → anti-aging. Activatable via NAD⁺ boosters

Loss of proteostasis

Misfolded/damaged/aggregated proteins → loss of normal function + toxic gain of function

Deregulated nutrient sensing

Pathways allocate resources between growth/reproduction vs stress/survival; evolutionarily conserved metabolic pathways also regulate aging

Cellular-Level Theories

Mitochondrial dysfunction

ROS + protein misfolding damage mitochondria, with impairment in heart/muscle/brain/adipose
Vicious cycle: ETC stray electrons + O₂ → superoxide → mtDNA damage (bacterial circular DNA, vulnerable) → defective ETC components → more ROS
Mitochondrial deletion hypothesis of sarcopenia: mtDNA depletion → no ETC → muscle atrophy
Rejuvenation: fasting → mitophagy clears unhealthy mitochondria → healthier mitochondria afterward

Cellular senescence

Accumulate with age. Stable cell-cycle arrest (stop dividing, don’t die), caused by DNA damage/ROS/telomere shortening
Altered morphology/expression/metabolism. Secrete inflammatory signals (SASP)
Tissue damage: senescent stem/progenitor cells → impaired regeneration, paracrine senescence, inflammation, and ECM remodeling/fibrosis

Stem cell exhaustion

↓stem cell function → tissue/organ dysfunction → aging phenotypes
Intrinsic (DNA damage, telomere shortening, senescence) + extrinsic (niche aging, chronic inflammation)

一問一答

▶Why is aging considered the largest risk factor for chronic disease?

Age-specific mortality rises exponentially, and aging outweighs other risk factors for heart disease and is the main risk for Alzheimer's.

▶How does genomic instability contribute to aging?

DNA alterations from ROS and replication errors cause mutations (cancer), chronic DNA damage (cell death), and senescence ('inflamm-aging').

▶How does declining stress resilience manifest in the elderly?

Slower return to equilibrium after stress, e.g., higher infection mortality.

▶What is the Hayflick limit and its relation to telomeres?

The ~50-division limit of somatic cell replication; progressive telomere shortening with each division is its underlying cause.

▶How is aging defined?

Progressive deterioration of physical function leading to declining health and increased mortality.

▶Is telomere shortening thought to be the cause of aging?

Likely not the cause of aging, but it is key in tumor protection.

▶What is telomerase and why is it relevant to cancer?

A reverse transcriptase that elongates telomeres; it is upregulated in cancer cells to bypass the Hayflick limit. Somatic cells lack it, undergoing replicative senescence.

▶What is the DNA methylation (Horvath's) clock?

CpG-island methylation increases with age and silences genes; Horvath's clock uses it to estimate biological age and the rate of aging.

▶What is the role of SIRT-1 in aging?

A sirtuin histone deacetylase (first pro-longevity gene) that reopens DNA for transcription, exerting anti-aging effects; activatable via NAD⁺ boosters.

▶What is loss of proteostasis in aging?

Accumulation of misfolded/damaged/aggregated proteins causing loss of normal function plus toxic gain of function.

▶What is deregulated nutrient sensing in aging?

Evolutionarily conserved metabolic pathways that allocate resources between growth/reproduction and stress/survival also regulate aging.

▶What is the mitochondrial deletion hypothesis of sarcopenia?

mtDNA depletion → no functional ETC → muscle atrophy.

▶Describe the mitochondrial vicious cycle in aging.

ETC stray electrons + O₂ → superoxide → mtDNA damage (vulnerable circular DNA) → defective ETC components → more ROS.

▶How does fasting rejuvenate mitochondria?

Fasting triggers mitophagy, which clears unhealthy mitochondria, leaving healthier mitochondria afterward.

▶What defines cellular senescence?

Stable cell-cycle arrest (cells stop dividing but don't die), caused by DNA damage, ROS, or telomere shortening, with altered morphology/metabolism and SASP secretion.

▶How do senescent cells damage tissues?

Senescent stem/progenitor cells impair regeneration and cause paracrine senescence, inflammation, and ECM remodeling/fibrosis.

▶What is the SASP?

The senescence-associated secretory phenotype — inflammatory signals secreted by senescent cells that drive paracrine senescence, inflammation, and fibrosis.

▶What causes stem cell exhaustion in aging?

Intrinsic factors (DNA damage, telomere shortening, senescence) and extrinsic factors (niche aging, chronic inflammation), leading to tissue/organ dysfunction.

▶What are the molecular hallmarks of aging?

Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and deregulated nutrient sensing.

▶What are the cellular hallmarks of aging?

Mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.