Insights

Aging is often painted as an inevitable decline, but research now suggests that many of the processes driving it are identifiable and, in some cases, modifiable.  As a physician, I see patients worry about losing their vitality.  Knowing why the body ages helps us focus our efforts on the changes that matter most.  Scientists have grouped these biological changes into nine so‑called “hallmarks” or “pillars” of aging.  Below is an overview of each hallmark, translated into everyday language, along with highlights from the latest evidence.

1. Genomic instability

Every day, your DNA is bombarded by toxins, radiation and by‑products of normal metabolism.  Our cells repair most of the damage, but over time errors accumulate.  A key example is mosaic chromosomal alterations (mCAs) – segments of chromosomes that are gained or lost in some blood cells.  A 2023 study of ~500 000 people found that mCAs become more common with age and often carry genetic changes that disadvantage the cell.  In other words, as you get older your cells’ “instruction manual” gets more dog‑eared.

2. Telomere attrition

Telomeres are protective caps at the ends of chromosomes.  Like the plastic tips on shoelaces, they prevent chromosomes from fraying.  Each time a cell divides, telomeres shorten slightly.  When they get too short, the cell either stops dividing or dies.  Studies in people with cardiovascular disease show that shorter leukocyte telomere length is linked to higher all‑cause mortality.  Some racial and sex differences exist, but overall shorter telomeres signal a cell that has reached its replicative limit.

3. Epigenetic alterations

DNA isn’t the whole story; chemical tags on DNA and its associated proteins act like dimmer switches, turning genes on or off.  These “epigenetic” marks change with age and environment.  Modern epigenetic clocks integrate multiple marks to estimate biological age.  The GrimAge and GrimAge2 clocks, for example, strongly predict mortality in large population studies.  Unlike telomeres, epigenetic marks can shift rapidly in response to diet, stress or pollution, which is why lifestyle interventions may influence biological age.

4. Loss of proteostasis

Proteins perform most of the work inside cells.  To function properly they must fold into precise shapes and be replaced when damaged.  Aging cells struggle to maintain this protein balance (proteostasis).  Heat‑shock proteins (HSPs) are a family of molecular “chaperones” that help other proteins fold and prevent misfolding.  Research shows that aging reduces the activity of heat‑shock factor 1, leading to fewer HSPs and impaired protein quality control.  Consequently, misfolded proteins accumulate, which is implicated in neurodegenerative diseases like Alzheimer’s and Parkinson’s.

5. Deregulated nutrient sensing

Cells use nutrient‑sensing pathways to decide whether to grow, divide or clean house.  The main pathways – mTOR, insulin/IGF‑1, AMPK and sirtuins – act like metabolic traffic lights.  Too much activation (e.g., from constant high blood sugar) accelerates aging; mild inhibition may extend healthy lifespan.

• mTOR: Inhibitors of mTOR (rapalogs) enhance immune responses in older adults and, in early trials, reduced respiratory infections .  A phase 3 trial, however, did not meet its primary infection endpoint, reminding us that tweaking these pathways is complex.

• IGF‑1: Both very low and very high blood levels of insulin‑like growth factor 1 (IGF‑1) are associated with increased cardiovascular risk, forming a U‑shaped curve.  Moderation appears key.

• AMPK & sirtuins: These energy sensors are activated by fasting and exercise.  Natural compounds like resveratrol stimulate them, but human trials show modest metabolic benefits at best.

6. Mitochondrial dysfunction

Mitochondria are the cell’s power plants.  With age, their DNA (mtDNA) can decline in copy number and accumulate mutations, impairing energy production.  In patients with peripheral artery disease, those with the lowest mtDNA copy number had a three‑fold higher risk of death .  Strategies to support mitochondrial function – such as regular exercise, avoidance of smoking and possibly supplementation with NAD+ precursors – aim to keep these power plants humming.

7. Cellular senescence

When cells experience too much stress or DNA damage, they may enter a state called senescence.  Senescent cells stop dividing but remain metabolically active, releasing inflammatory molecules known as the senescence‑associated secretory phenotype (SASP).  They accumulate with age and at sites of chronic disease.  Excitingly, small pilot studies have tested drugs called senolytics that selectively clear senescent cells.  In an open‑label trial, three days of dasatinib plus quercetin in individuals with diabetic kidney disease reduced senescent cell markers (p16 and p21) and inflammatory SASP factors in fat tissue and skin .  The treatment acted like a “hit‑and‑run” – short exposure lowered senescent cell burden for weeks .  Larger, placebo‑controlled trials are ongoing.

8. Stem cell exhaustion

Our bodies rely on stem cells to replenish tissues.  With age, stem cell numbers and diversity decline.  In hematopoietic stem cells (HSCs), this phenomenon contributes to clonal hematopoiesis of indeterminate potential (CHIP).  By age 75, just a dozen or so HSC clones may supply most blood cells .  CHIP confers increased risks: carriers have roughly twice the risk of coronary heart disease and up to four times the risk of myocardial infarction .  A recent UK Biobank study following over 370 000 individuals found that people with CHIP had higher hazard ratios for developing a first cardiometabolic disease and for mortality, especially when variant allele fractions (VAFs) exceeded 10% .  Monitoring and, eventually, intervening on CHIP may become part of preventive cardiology.

9. Altered intercellular communication

Aging tissues exhibit inflammaging – chronic, low‑grade inflammation that disrupts communication between cells.  A meta‑analysis of 22 studies showed that older adults with comorbidities have significantly higher circulating interleukin‑6 (IL‑6) levels compared with healthy controls .  IL‑6 helps orchestrate immune responses but in excess contributes to frailty and chronic disease .

Two additional areas of interest are extracellular vesicles (EVs) and the microbiome:

• Extracellular vesicles: These nano‑sized packages shuttle proteins, RNA and lipids between cells.  EVs from young plasma reversed molecular and physiological aging in old mice, partly by boosting mitochondrial regulator PGC‑1α .  Blood‑derived EVs may serve as non‑invasive biomarkers, but isolating them is challenging because they are mixed with plasma proteins and lipoproteins .

• Gut microbiome: Fecal microbiota transplantation (FMT) can remodel the gut ecosystem.  In a randomized trial involving women with metabolic syndrome, FMT changed the gut microbiome but did not improve metabolic markers such as weight, glucose or insulin resistance .  Current evidence suggests FMT’s benefits are condition‑specific (e.g., for recurrent C. difficile infection) and that robust protocols are still being developed.

Bringing it all together

The hallmarks of aging are interconnected.  Genomic instability can trigger telomere erosion and epigenetic drift; mitochondrial dysfunction can provoke proteostatic stress and inflammaging.  While no single intervention can “stop the clock,” understanding these processes empowers us to make evidence‑based choices.  Regular physical activity, balanced nutrition, adequate sleep and stress reduction support mitochondrial health, maintain proteostasis and temper chronic inflammation.  Emerging therapies targeting mTOR, senescent cells or clonal hematopoiesis offer hope, but they remain under study.

I will continue to watch this field closely.  Our goal is not to chase immortality but to maximise healthspan – the years of life free from disease and disability.  By staying informed and adopting healthy habits, we can make the most of the years we are given.