#how does aging work

In 1993, molecular biologist Cynthia Kenyon and her colleagues published a revolutionary study demonstrating that mutating a single gene in the worm C. elegans doubled its lifespan. Compared to control worms, the mutant worms appeared younger by several key metrics. The landmark study fundamentally proved that aging is not an unchangeable, random biological process but a process driven by mechanisms that can be studied, influenced, and slowed. Kenyon's research marked the beginning of the modern study of biological aging (known as geroscience). Since then, research labs and companies have sprouted around the world aiming to research and rethink what it means to grow older.

Kenyon's findings came at an important moment in history. Since the beginning of the 1900s Human lifespans have more than doubled, largely because of public health initiatives such as access to chlorinated water, vaccines, and penicillin. These initiatives helped to eradicate many of the deadly diseases that have historically shortened human lifespans. Now, more people are reaching old age than at any point in history, and the new challenge is helping them stay healthy as they get older.

Researchers recognize that to treat age-related diseases like cancer, Alzheimer's, and cardiovascular disease, it is important to examine why these diseases develop in the first place. By understanding the mechanisms that drive cellular aging, and how these mechanisms differ from person to person, therapies can be developed to prolong human longevity and stop aging-related diseases before they develop.

Aging Mechanisms

Through aging research, scientists have found several interconnected processes that lead to the loss of cellular integrity over time. The following factors are well-documented drivers of the biological aging process.

Genomic Instability

Many age-related diseases are caused by the accumulation of mutations in our deoxyribonucleic acid (DNA) as we grow older. Changes in the genome—the complete set of DNA and genetic instructions found within a cell—have a significant effect on how an individual ages. Human DNA is continually exposed to stressors such as ultraviolet radiation. Ultraviolet radiation is a well-known mutagen that has been proven to cause structural damage or photolesions to DNA, which can stall the machinery involved in DNA replication and cause polymerases to form incorrect base pairs. Disregarding environmental influences, the standard DNA polymerase responsible for replicating new DNA strands makes one error in every 10 billion base pairs. A typical human cell, in its diploid state with two paired sets of 23 chromosomes, contains approximately 6.0 – 6.4 billion base pairs of DNA. Across the human lifespan, the body will replicate roughly 10 quadrillion base pairs. For the most part, DNA polymerase can self-correct errors, but occasionally an error bypasses these repair mechanisms and becomes a permanent mutation.

As a person ages, the number of permanent mutations in the genome accumulates. At the same time the accuracy of the body’s DNA repair systems naturally begin to decline. With more problems to repair and fewer resources to repair them, mutations rates and damage to the DNA compound with age. The rise in genomic instability is considered a primary hallmark of aging, as it leads to cellular dysfunction that impairs organ and tissue health. As people continue to live longer, there is more time for genetic damage to accumulate and a higher chance that a mutation in the DNA will manifest as a disease.

Telomeres

While mutations accumulate over a person’s lifetime, there is a separate internal clock that dictates the lifespan of any given cell lineage. During somatic cell division, DNA polymerase is responsible for duplicating the genetic material within a cell. However, in the copying process, DNA polymerase requires an RNA primer to initiate DNA synthesis and as a result the final section of the lagging strand of DNA cannot be fully replicated. Because the DNA polymerase is unable to fully replicate the ends of linear chromosomes, gradual chromosome shortening occurs with each cell division. To prevent the loss of important coding DNA, the ends of chromosomes have a protective cap composed of repeating non-coding sequences called telomeres. The incomplete replication of chromosomal ends does not result in damage to the genome because telomers act as disposable buffers. However, telomers shrink considerably after repeated rounds of cellular division.

When telomeres become too short, cells enter a state of permanent arrest called replicative senescence; a state in which cells remain metabolically active but can no longer divide. Replicative senescence acts as a biological failsafe to prevent cells with seriously shortened telomeres or unstable DNA from replicating. In 1961, Leonard Hayflick demonstrated that normal human cells can divide about 40 to 60 times before becoming senescent; a biological milestone now described as the Hayflick limit. Senescent cells secrete a harmful cocktail of molecules known as the senescence-associated secretory phenotype (SASP). Though transient SASPs are essential for recruiting immune cells and repairing tissue damage, the chronic sustained secretion of SASPs creates a chronic low-grade inflammation state that causes systemic tissue decay.

Mitochondrial Dysfunction

Mitochondrial dysfunction and the cellular and tissue damage it causes is one of the hallmarks of cellular senescence. Mitochondria are unique organelles, or specialized, functional subunits within a cell, that have their own DNA. Mitochondria convert nutrients from food and oxygen into adenosine triphosphate (ATP)—the cell’s primary source of energy that fuels nearly all biochemical processes in the human body. In a dynamic process called fission-fusion balance, mitochondria continuously divide and merge to adapt to cellular and metabolic needs, repair damage, share resources, and maintain organelle health. As mitochondria accumulate mutations in their DNA, and as the balance between fission and fusion dynamics breaks down, their ATP output falls. This plummet in ATP releases reactive oxygen species (ROS) that damage DNA and push cells toward senescence. Senescent cells then secrete SASP causing damage to neighboring cells which creates a cascade effect.

The declining NAD+/NADH (Nicotinamide Adenine Dinucleotide + / Nicotinamide Adenine Dinucleotide + Hydrogen) ratio that accompanies mitochondrial deterioration activates AMPK (AMP-activated protein kinase) which reinforces the senescent state by activating tumor suppressor pathways p53 and p16. These factors create a reinforcing cycle where senescent cells with dysfunctional mitochondria accumulate and create chronically inflamed microenvironments. The collapse that occurs in mitochondria dysfunction when cellular energy plunges, oxidative stress spikes, and cells can no longer discard damaged organelles is a key driver of age-related diseases like Parkinson’s and Alzheimer’s.

Epigenetic Alterations

ROS released by dysfunctional mitochondria—like superoxide radicals and hydrogen peroxide—can alter the epigenome. The epigenome is the system of chemical tags present on chromatin that act as on on/off switch to regulate when and how strongly genes are expressed without altering the genetic code itself. The epigenome controls the remodeling of the macromolecular complex of DNA, RNA, and proteins called chromatin that condenses to form the chromosomes present in cells of all eukaryotes including human beings. The remodeling of chromatin becomes deregulated with age, and genes that should remain silent may become active while genes that should be expressed can get turned off.

The disruption of mechanisms that control gene expression—chromatin remodeling, histone modification, and DNA methylation—is called epigenetic dysregulation. Epigenetic dysregulation can lead to improper gene activation or silencing leading to genomic instability, abnormal gene expression, and severe diseases such as cancer. Because epigenetic changes don't change the genome, they are potentially reversible which makes the epigenome an attractive target for therapies aimed at reversing biological aging.

The Decline of Proteostasis

The misfolding of protiens is one of the potential downstream effects of epigenetic alterations. Cells depend on a quality control system called proteostasis to maintain a healthy population of proteins. In the process of proteostasis, molecular chaperones make sure that proteins fold into the correct three-dimensional shapes while degradation mechanisms—like the ubiquitin-proteasome system—identify and discard damaged proteins. With age, the efficiency of proteostasis declines significantly, preventing misfolded proteins from being degraded and allowing them to clump and aggregate within cells. Loss of proteostasis is a hallmark of aging and a primary driver of neurodegenerative diseases. Several studies have found that modifying proteostasis networks can increase both lifespan and healthspan in mammals, suggesting it is a legitimate target for anti-aging interventions.

Nutrient-Sensing Pathways

To maintain homeostasis, cells must regulate internal cellular processes while also monitoring extracellular nutrient levels to translate nutrient availability into metabolic instructions that manage cellular growth, energy production, and survival. Cellular nutrient sensing acts as a metabolic command center that relies on protein pathways to read both extracellular and intracellular nutrient levels and issue instructions based on what those pathways find. When nutrients—like amino acids, glucose, and lipids—are plentiful, cells activate anabolic pathways to build macromolecules and store the nutrients. When nutrients are scarce, catabolic pathways break down those macromolecules and release energy to fuel cellular operations. Damaged nutrient-sensing pathways can impair cellular metabolism and lead to the overproduction of ROS or even cellular death if the cell cannot acquire sufficient nutrients.

Two proteins fundamental in the governance of cellular metabolism are Akt (Protein kinase B) and AMPK. Akt is a serine/threonine kinase and a core component of the PI3K/Akt signaling pathway that promotes cell proliferation and survival in response to extracellular signals. AMPK is a master regulatory protein that detects cellular energy through the AMP (adenosine monophosphate) to ATP (adenosine triphosphate) ratio. When nutrients are abundant, Akt facilitates cell growth and activates anabolic pathways to store energy. One example of this is after a meal. As food is digested, blood sugar rises, and the pancreas releases insulin. The insulin travels through the bloodstream to target tissues like muscle, liver, and fat, where it binds to specific insulin receptors and activates Akt inside the cell. Once activated, Akt facilitates glucose uptake into the cell to lower blood sugar and store the surplus sugar.

While Akt helps store energy, AMPK helps release energy by sensing when the body’s energy levels are low within a cell and activating catabolic pathways in response, allowing cells to break down and use stored energy when your body needs fuel. When AMPK detects low cellular energy, it responds by slowing cell growth and activating energy-conserving processes. Under energy-replete conditions, AMPK is inactivated via dephosphorylation, ceding metabolic control to Akt and its downstream effectors. The balance between Akt and AMPK governs cellular metabolism, moving the cell towards storage and growth (anabolism) when external nutrients levels are high and moving the cell towards energy release (catabolism) when nutrient levels are low.

The interplay between Akt and AMPK also influences the body's cancer suppression system through the p53 tumor suppressor gene. Known as “the guardian of the genome,” p53 is a protein that protects DNA by preventing damaged cells from dividing. The process of cell division involves a series of checkpoints where the cell pauses to confirm it is fit to continue. At one of the checkpoints, the cell checks if it is healthy before copying its DNA, and at a later checkpoint, the cell checks that the copying was done correctly before it divides. When a cell fails a check, p53 switches on a cyclin-dependent kinase inhibitor called p21, which blocks the cell from entering the next stage of the cycle.

Because active p53 is so disruptive to cell growth, healthy cells keep its levels low by using a protein called MDM2, which tags p53 for degradation. MDM2 inhibits p53 by inciting E3 ubiquitin ligase activity to mark p53 for proteasomal degradation. Akt aids this process by phosphorylating MDM2 at Ser166 and Ser188 (in humans), promoting its nuclear translocation and interaction with p53. AMPK works in the opposite direction, inducing p53 activity primarily through direct phosphorylation of p53 at Ser15, which stabilizes it against MDM2-mediated degradation. The cells that p53 holds back are often the ones carrying DNA damage that builds up with age, so the system checkpoint acts as a defense against age-related cancer. However, p53 can be a double-edged sword. Though the protein protects from cancer, the overactive production of p53 can cause premature aging and tissue damage.

Stem Cells

Stem cells are specialized cells capable of dividing to regenerate or transform into specific, operational cell types (like blood cells, bone cells, brain cells, muscle cells, or nerve cells). The body relies on undifferentiated stem cells to repair and replace damaged cells in the tissues and organs. Through the three-step process of activation, proliferation, and differentiation, stem cells serve as the body’s internal repair system and as foundational raw materials for the body to mold into action. By dividing into identical stem cell copies or transforming into specific cell types, stem cells can restore tissue function and replace dying, damaged, or aging cells over an organism’s lifetime.

Stem cells normally remain in a quiescence (dormant) state. However, as we age, tissue damage and chronic inflammation, can force stem cells from their dormant state into a hyper-activated state of cell division to repair the body. Repeated cell divisions subject stem cells to telomere attrition, the accumulation of genetic mutations, and epigenetic dysregulation. To prevent the unregulated proliferation of potentially cancerous cells, Stem cells enter a state of exhaustion where their regenerative capacity falters. Stem cell exhaustion, or the gradual loss of stem cell regenerative capacity and function, is a primary hallmark of aging and leads to increased age-related diseases, tissue deterioration, and impaired healing.

Intercellular Communication

Cells communicate through several mechanisms, most involving a signaling molecule and a receptor. However, several of these pathways break down with age. Senescent cells secrete inflammatory microRNA cargo that signals dysfunction to neighboring cells throughout the body. Oxidative damage and epigenetic silencing close gap junctions that facilitate direct molecular communication between cells. SASP factors also desensitize hormone receptors, causing hormonal signals to produce frailer responses within the cell. This creates a weaker coordinated response to cellular damage. This is part of the reason why aging tends to accelerate across the body simultaneously rather than just occurring locally.

Hormonal Decline

Just as cells require signal pathways to communicate, organs from different parts of the body need to communicate, like the stomach telling the brain that you are full. Hormones serve as the primary signaling molecules that carry messages between these distant parts of the body. The endocrine system regulates the body’s internal homeostasis by releasing hormones into the bloodstream in response to internal or external changes. With age, cells become less responsive to these signals, and the hormones themselves are released in smaller amounts and weaker pulses.

The hypothalamic-pituitary axis, the primary neuroendocrine system in the body, becomes less sensitive to feedback signals over time, reducing the pulsatile release patterns that drive downstream hormone production. Testosterone declines gradually from the third decade onward, reducing the anabolic signaling that maintains muscle mass and bone density. Estrogen loss in women at menopause removes a key suppressor of bone resorption and a regulator of cardiovascular inflammation. DHEA (dehydroepiandrosterone—a natural hormone produced by human adrenal glands) peaks in the mid-twenties and falls more steeply than almost any other hormone across the human lifespan. Human growth hormone (HGH), or somatotropin—a natural protein produced by the pituitary gland—drives bone growth and height in children, builds muscle mass, maintains bone density, and regulates metabolism and body fat distribution in adults.

In a process called somatopause, the production of HGH and Insulin-like Growth Factor 1 (IGF-1) decline with age. IGF-1 acts as a master coordinator to drive cellular anabolism and pair cellular growth and survival to the physical environment and the body’s metabolic state. The progressive decline in IGF-1 levels slow cellular repair, metabolic processes, and protein synthesis. As these signaling molecules decline the body loses an important measure for cell signaling and maintaining homeostasis in response to the environment.

Dysbiosis

Despite regulating up to 80% of the immune system and weighing a whopping 2 to 5 pounds, the gut microbiome is one of the most overlooked aspects of health. The community of bacteria living in your intestines shifts with age becoming less diverse and less balanced. One reason for this is changing diets as people age. Dental problems make foods like vegetables and legumes harder to chew, reduced mobility can make cooking less practical, and a declining sense of taste and smell can make food less appealing. The result is that older adults often eat less fiber compared to their younger counterparts.

Several beneficial bacteria that reduce inflammation and strengthen the gut lining depend on fiber to survive. As fiber consumption decreases, useful bacteria get crowded out by more resistant bacteria, which can trigger a phenomenon called inflammaging. As inflammatory bacteria start to dominate, the mucosal lining of the gut can begin to degrade, allowing harmful bacteria to slip through the intestine wall and into the bloodstream. This bacterial translocation produces chronic, low-grade inflammation that accelerates aging throughout the body. The loss of beneficial microbes, an overgrowth of harmful microbes, and an overall decline in microbial diversity is characteristic of dysbiosis, or the imbalance in types and functions of microorganisms (like bacteria or fungi) within a bodily microbiome like the gut. Scientists consider dysbiosis a hallmark of the aging process.

Immunosenescence

The inflammation produced by dysbiosis often occurs in parallel with immunosenescence—the gradual deterioration of the immune system that occurs with age. As we age, the immune system becomes more inflammatory and less effective. The accumulation of SASPs activates chronic immune signaling that locks the defense system in a continuous state of high alert and that triggers low-grade inflammation. As thymic tissue in the thymus gland is gradually replaced by fatty tissue, a process known as thymic involution, the production and diversity of naïve T cells is restricted, reducing the efficacy of the immune system and leaving the body less capable of responding to pathogens. The process of immunosenescence begins in early adulthood and accelerates through midlife. This is why influenza vaccines generate protective immunity in 70 to 90 percent of younger adults but only 30 to 50 percent of people over 65. A narrower immune toolkit is also less capable of surveilling for early cancer and clearing senescent cells, which allows both to accumulate faster.

How Aging Differs Across Individuals

These and other factors influence how humans age. However, biological aging differs significantly across populations. Variations in how we age are the result of hereditary and environmental factors.

Genetics

Genetics accounts for approximately 25 percent of the variation in the biological aging process. Genetics largely determines how resilient cells are to damage over time and how well repair mechanisms function after stress. Studies of centenarians in Italy have found that many come from families with favorable immune and inflammatory gene variants that protect against cardiovascular disease and other age-related conditions. CRISPR-Cas9, a gene editing technology developed by biochemists Jennifer Doudna and Emmanuelle Charpentier, allows for precise, programmable editing of DNA. CRISPR functions like molecular scissors, offering a promising way to target genetic mutations and mitigate the gap between inherited genetic predispositions and the onset of age-related pathologies.

Environmental Exposures

The environment a person lives in can shape how quickly aging mechanisms activate. Living in poor conditions, such as homes contaminated with mold, can trigger chronic immune activation and persistent inflammation. Constant psychological stress from home or work elevates inflammation through the same pathways. Limited access to quality healthcare allows preventable damage to accumulate over time. Other variables such as exposure to ultraviolet radiation can cause a process called photoaging, which can break down elastin and collagen in the skin, producing wrinkles, pigmentation, and sagging. Exposure to first- or second-hand smoke can introduce potent toxins and heavy metals into the bloodstream, accelerating cellular senescence and the aging of the lungs and vascular network. The inhalation of air pollution can generate ROS within the body, weakening the lungs and leading to systemic inflammation. Prolonged exposure to heavy metals (like lead and cadmium) and synthetic chemicals (like benzene) found in tainted food and industrial products is closely associated with accelerated biological aging. Exposure to agricultural and domestic pesticides is also associated with increased biological aging and risk of age-related neurodegenerative disease.

Lifestyle

Personal lifestyle choices also influence how individuals age. Positive habits include whole-food diets, especially those rich in fiber and anti-inflammatory foods like berries, legumes, and green leafy vegetables. Furthermore, exercise and proper sleep (8 hours per night on average), when coupled with improved eating habits, create a synergistic effect by promoting glucose regulation within the body. On the other hand, smoking and heavy drinking can damage the DNA and drive chronic inflammation. When coupled with poor sleep and eating habits, this can accelerate the onset of many health problems within one's lifetime.

Although it is recommended that every individual strive for a balanced diet and sleep schedule, such healthy lifestyle choices are not equally available to everyone. Approximately 19 million to 40.5 million Americans live in USDA-designated food deserts, meaning that they have limited access to fresh, nutritious, and affordable food. Many of these individuals also reside in low-income neighborhoods, which have a disproportionate number of adults working two or more jobs to make ends meet for their households. These conditions cause stress, lack of sleep, and exposure to harmful environmental factors—all of which hasten the development of early onset health problems. Aging is as much about the conditions in which a person lives as it is about biology, and these conditions are not handed out evenly.

Conclusion