Patient explainer · Learn
The hallmarks of aging.
This is a detailed subject, and what it means for your health depends on your history and your goals. Dr. Glowney is glad to work through it with you.
New ideas about aging and interventions to influence it have been proposed in fields including DNA repair and cellular recycling, inflammation, tissue mechanics, and social connection. Two individuals may have the same anniversary of birth but different health statuses. One individual with current or past health problems may be an otherwise healthy, mentally competent adult. Another individual with current or past health problems may have a low level of independence and other health problems. Anniversaries of birth reflect the passage of time since birth, not current health status.
The connection between aging and disease is an area of study called geroscience, which explores biological connections between aging and disease. Geroscience has many potential benefits, including multiple health benefits from interventions that affect many diseases.
Hallmarks of aging provide a framework for testing this hypothesis. First described in a 2013 Cell review article by Carlos López-Otín and others, nine hallmarks of aging were recognized. Three more hallmarks of aging were described in a review article published in Cell in 2023. Two other hallmarks of aging, extracellular matrix changes and psychosocial isolation, were proposed in a 2025 aging review article. [1-4] These new findings are not simply incremental knowledge contributions related to aging but enhance overall understanding of aging processes, such as new knowledge about intracellular and other protein processes and interspecies interactions, such as human-microbial and human social interactions.
The hallmarks of aging may offer valuable information for researchers interested in extending life. Healthcare professionals interested in using this information should understand current knowledge and gaps regarding the hallmarks and other potential uses for humans informed by research on other species.
A framework for asking better questions.
The original article on hallmarks of aging was published at a time when research on experimental aging was expanding. Findings indicated that some genes and other mechanisms related to aging could be manipulated to extend lifespan in other species. Attitudes about aging had changed from viewing aging as a process of random damage to viewing it as something that can be at least partially controlled.
López-Otín and others proposed three requirements for processes to be considered hallmarks of aging. The hallmark process changes with aging. Experimental manipulations that worsen the hallmark process lead to accelerated decline of aging-related functions. Experimental manipulations that improve the hallmark process ameliorate some symptoms of aging or extend health span. [1, 3]
The third item is important. Having a biomarker that changes with age is not the same as having a drug target for age-related conditions. Gray hair is a biomarker of aging, and changing hair color will not restore physiological resilience. Other molecular biomarkers of aging should not automatically be considered potential drug targets.
Even if the process is involved in aging, finding ways to manipulate it safely in humans is a separate issue. Research on cells and other model organisms, including worms and mice, has identified biological processes that may also extend health spans in humans, but this research does not demonstrate that these processes can be used to extend health spans in humans.
The framework also has other broad categories. Examples of hallmark traits involving damage include traits that contribute to the accumulation of damage. Other hallmark traits are helpful at low exposure levels but harmful at higher exposure levels or over the long term. Other hallmark traits are failures to maintain and coordinate tissues. [1, 3] This difference clarifies a paradox; things that contribute to aging in organisms also have other benefits for them.
Preservation methods: DNA, telomeres, and epigenetics.
1. Genomic instability
All cells require intact genetic material. DNA damage can be caused by a variety of factors, including mistakes during normal cellular processes and environmental exposure to toxic or other chemicals.
Cells have repair processes, but damage can escape repair or be repaired incorrectly. Accumulation of mutations and other chromosomal abnormalities occurs over time. Health effects associated with these abnormalities include apparent lack of health effects and disruption of usual cell and tissue functions and higher cancer risk.
There is a major distinction between inherited and acquired genetic variants. Inherited genetic variants may make an individual susceptible to disease from birth. Acquired genetic variants result in differences among cells of the same individual, also called somatic mosaicism.
Genomic instability is a major underlying cause of aging, cancer, and other stem cell-related and inflammatory diseases. The model supports the value of reducing risk factors for age-related and other diseases, as well as therapeutic approaches to mitigate DNA damage responses. [1, 3]
2. Telomere attrition
Telomeres are regions at the ends of chromosomes that prevent chromosome ends from being mistaken for broken DNA. Telomeres are believed to shorten every time a cell divides. Cells with critically short or damaged telomeres typically stop dividing or undergo apoptosis.
This process may limit tissue repair. Decreased cell division also helps defend against cancer. The enzyme telomerase protects telomeres, and multiple types of cancer exploit telomerase to aid cancer cell proliferation. Longer telomeres are not always desirable. Species face costs and benefits of telomere maintenance and regeneration related to cancer.
Telomere research has applications to rare diseases and aging. Other research on telomeres indicates that it would be inappropriate to promote a dietary supplement or diagnostic test measuring telomere length to predict lifespan in an individual. [1, 3]
3. Epigenetic alterations
Cells with the same DNA can become neuron cells, muscle cells, or immune cells due to variations in gene expression. Epigenetic factors enable individual cells with the same DNA to produce different proteins. Aging is linked to changes in the histone and chromatin structure and DNA methylation. These changes in histone and chromatin structure and DNA methylation can lead to changes in gene expression and cell identity. Certain methylation-based biomarkers of aging are accurate enough to build "epigenetic clocks" that can predict things about an individual's life, including chronological age and disease risk, depending on how they were developed.
The ability to use measurements to predict outcomes does not prove that all changes in measurement are related to outcomes associated with aging. Proving that a clock-like device can display younger age does not prove that a person has better health outcomes. Interventions to change measurements should be tested separately for clinical benefit. [3]
When protective behaviors are long-term problems.
8. Cellular senescence
Cellular senescence is a stress-induced proliferative and functional arrest of cells. Advantages of cellular senescence include anticancer and tissue repair properties. Problems arise from the inability of the immune system to clear senescent cells or the accumulation of senescent cells in tissues. Senescent cells produce multiple proteins, including growth factors and proteases, in a senescence-associated secretory phenotype that can damage tissues. These signaling molecules can affect neighboring cells and contribute to mechanisms that link cellular senescence with inflammation, fibrosis, and impaired tissue repair.
Clearing senescent cells has positive effects in some animal studies, pointing to potential advantages of senolytic therapies. Limited and conflicting data exist about senolytic effects in humans. In a randomized study, postmenopausal women (n = 60) taking dasatinib and quercetin for 20 weeks did not show significant benefit on the primary bone-resorption outcome, while other study results and subgroup analyses were encouraging and suggested the need for further study. Key differences exist between a compelling target and an established treatment. [5]
9. Stem cell exhaustion
Many tissues have stem cells and other cell types that play a role in repairing and regenerating damaged tissue. Aging can affect the number and function of stem cells and other cell types in many tissues and impair the body's ability to repair tissue damage.
The environment around the injured tissue contributes. Inflammation, altered physical properties of surrounding tissue, and other responses in neighboring cells can block healing. Stem cell depletion isn't simply about a lack of stem cells. Stem cell regeneration depends on interactions between tissues and cells.
This distinction is important when considering the promise of regenerative therapies. Defective stem cell function observed in a disease is not necessarily an indication that there is a safe and effective therapy using transplanted stem cells or other therapies such as transplantation of extracellular vesicles or secretome components. [1, 3]
Communication across cells, organs, and microbes.
10. Altered intercellular communication
A healthy body functions as an integrated unit. Organs communicate with the nervous and endocrine systems, immune system, and other organs to respond to the body's needs. As we age, changes occur in signal pathways. Signals involved in repair can become persistent. Signals that normally resolve may remain active. Tissues may no longer respond to beneficial signals.
The 2013 framework identified changes in communication as a general feature. The 2023 update maintained this feature but added chronic inflammation and dysbiosis as specific features to draw more attention to them. [1, 3] This gives a mechanism by which disorders of one organ can influence others. Age-related changes occur in a localized manner and affect associated organ systems.
11. Chronic inflammation
Inflammation is protective and restorative for tissues. Inflammaging is age-related inflammation that can contribute to tissue dysfunction. Contributors to this process may include cellular senescence, mitochondrial dysfunction, immune system changes, metabolic dysfunction, and disruption of barriers. Increased inflammation and decreased protection from infectious diseases frequently coexist, but increased inflammation is not associated with increased protection from infectious diseases.
Human studies indicate that inflammation could be a therapeutic target. In the randomized CANTOS trial, treatment with the anti-interleukin-1β monoclonal antibody canakinumab reduced recurrent cardiovascular events in high-risk individuals with previous myocardial infarction and elevated inflammatory biomarkers. Fatal infections were more frequent among canakinumab-treated patients, but total deaths were not significantly reduced. [6]
The purpose of this treatment is to modulate the immune system. Treatments are specific and used for certain medical conditions.
12. Dysbiosis
The human microbiome performs functions such as aiding digestion and metabolite production and interacting with the host immune system and other tissues. Many factors affecting changes in the microbiome associated with aging include diet, pharmaceuticals, other health conditions, and the health of host tissues.
Dysbiosis does not have a characteristic microbiome signature. The microbiomes of healthy people vary by individual and group, and the meaning of particular microbes depends on their biological context. Human studies on nutrition have found evidence of a dynamic relationship between the microbiome and the immune system. A Stanford pilot study found that eating fermented foods increased diversity and reduced inflammatory markers among study participants. The study did not measure other health outcomes, such as longer life. [7]
The microbiome is an area of interest for research on aging. Other commercial microbiome-related tests and products will need to show clinical benefits.
Why the framework continued to expand.
A 2022 conference report from Copenhagen urged researchers to consider other hallmarks of aging in addition to the original nine. These and other potential new hallmarks were discussed at the conference in Copenhagen, including autophagy defects, microbiome defects, inflammation, RNA processing defects, and physical changes. [2] Its main point is that applicable frameworks should be adaptable to change. Other processes and considerations should not be disregarded simply because they are not part of a framework diagram.
RNA processing is one example. Other RNA processes are important for making proteins in cells. Other RNA-related processes, such as RNA splicing, may be important in aging, though they were not discussed separately in the 2023 review of hallmarks of aging.
Hallmarks described in the 2025 Cell review article include extracellular matrix changes and social withdrawal, among others, in addition to hallmarks mentioned earlier. [4]
Extracellular matrix changes
The extracellular matrix consists of materials, including collagen and elastin, that cells produce and lay down outside themselves. It provides structural and other types of support and communication for cells through mechanical and chemical signaling.
The extracellular matrix changes as an individual ages. Fibrosis and cross-linking of the extracellular matrix impact a variety of processes, including vascular function, regeneration, and cell signaling, as well as tissue mechanics. This application considers other cell-related factors in addition to genetics. The application could help establish new connections between research on cell aging and prevalent diseases and conditions, such as stiff blood vessels and difficulties healing wounds.
Psychosocial isolation
The new psychosocial isolation criterion expands molecular taxonomy. Psychosocial influences can affect psychophysiological and behavioral responses, sleep, and stress. The relationship is circular. Hearing loss, impaired mobility, cognitive decline, and depression are among the issues that reduce engagement. Decreased engagement can worsen hearing loss, impaired mobility, cognitive decline, and depression.
Psychosocial isolation is different from physical isolation. Social contact measures are not good ways to assess psychosocial isolation. This paper discusses the biological literature on the importance of psychosocial relationships and identifies research and policy gaps related to this area. These additions are suggestions in an active area of scientific research. They are not meant to indicate that all aspects of aging are completely understood. [4]
The hallmarks act as a network.
One common thread in the four seminal papers is interdependence. Possible sequence of events: Mitochondrial and other cellular abnormalities trigger inflammation. Inflammation alters the stem cell niche. Abnormal wound healing and other structural and mechanical tissue changes can promote additional cellular stresses and senescence.
Senescent cells can contribute to inflammation and matrix remodeling, reinforcing this process. These associations highlight multiple hallmarks affected by a single intervention and possible negative consequences of intervening in one hallmark. Interventions that promote cell growth can help heal injured tissues and increase cancer risk. Interventions that reduce inflammation can reduce tissue injury and weaken infection defense.
A diagram with separate segments can help explain these ideas, but aging should not be treated as a set of separate problems, each with its own product.
What is known in humans?
The best explanation of the hallmarks model is that there are intervention points in human aging. Other challenges include predicting which interventions will help humans, for whom, and at what cost.
One example is rapamycin. A large study of genetically diverse mice found that treatment with rapamycin extended lifespan in mice treated late in life. Studies like this one suggested that drugs targeting the mTOR pathway might be relevant to human aging research. They did not provide evidence in support of the claim that prophylactic treatment with rapamycin would extend human lifespan. [8]
Caloric restriction provides additional evidence. In a post hoc analysis of existing data from the two-year CALERIE randomized trial, there were small changes in DunedinPACE, an epigenetic measure of aging rate, in response to caloric restriction. Other measures of biological age, PhenoAge and GrimAge, were not altered by treatment in the CALERIE trial. The CALERIE study did not establish that participants would live longer. [9] These results are valuable because they can be easily communicated. They offer evidence of a biologic effect and other information that could help with study planning for studies with larger samples and longer follow-up periods. They are not strong enough evidence to support the conclusion that biologic effects observed in a laboratory setting indicate slower aging.
There is direct evidence of successful interventions that address problems people experience. Results from the LIFE trial indicate that structured exercise programs can help prevent major mobility problems in at-risk older adults. Pahor et al. did not need to demonstrate that all elements of mobility disability were corrected to show that their intervention was helpful. [10]
Longevity medicine can use findings from both mechanistic studies and clinical trials that demonstrate clear benefits.
Measuring aging without mixing up measures and objectives of aging research.
Biological age testing is appealing because it can provide a straightforward answer to a complex question about aging. Different tissues and cells age at different rates. A blood clock can give you information about disease risk and immune cell types but not as much information about cartilage and skeletal muscle cell types and brain cell types. Many clocks with different predictive values can be created. These clocks do not need to be consistent with one another.
In addition to distinguishing between older and younger groups, other features of clinically useful biomarkers include validation research and information about their reproducibility, responsiveness to intervention, and relationship to future outcomes. A biomarker can serve as a risk factor even if it is not a well-validated surrogate endpoint. A biomarker can serve as a surrogate endpoint if changes in response to treatment reliably indicate improved outcomes that matter. This is stronger evidence. [11]
Biological age tests can have a place in clinical care. Their results should be used with other clinical information, including symptoms and other risk and reaction information about diseases. Information about better clock function should not be given greater weight than other clinical information about reduced well-being and nutrition and quality of life.
From geroscience to precision geromedicine.
The 2025 review suggests ways to assess an individual's particular aging-related vulnerabilities in the future using biomedical, genetic, molecular, psychosocial, and other types of information. [4] The authors use gerogenic to describe harmful mechanisms and gerosuppressive to describe protective mechanisms. The authors hope to connect mechanisms to clinical practice.
Its benefits are considerable, but having more information about patients does not always improve care. Diagnostic tests can aid medical decision-making and help patients. Molecular information about patients can open up new treatment possibilities but also result in other diagnostic tests and treatments that are not helpful to patients.
Precision geriatric medicine needs to be studied prospectively. What are the benefits of molecular and other tests and approaches in precision geriatric medicine compared with a complete medical history, physical exam, and other evidence-based screening and prevention measures? For which older adults do these tests and measures work best? How can the benefits of precision geriatric medicine be delivered more efficiently and equitably?
These questions involve clinical trials. They are not problems that an advanced testing system can solve. For current health care practice, knowledge of the hallmarks of aging is useful for many clinical purposes but should not be used alone to deliver health care. Advantages of knowledge about the hallmarks of aging include a better understanding of complex biological phenomena, of what leads to earlier disability, and of protective factors. Discussion of the hallmarks of aging may be useful when discussing novel therapies with patients.
The practical goal of living a healthy, productive life includes preserving cognitive and physical abilities and resources that allow people to live productively. Research on hallmarks can support this goal by identifying ways to treat people and help them maintain their health and independence.
References
Sources cited.
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013;153:1194–1217. DOI: 10.1016/j.cell.2013.05.039.
- Schmauck-Medina T, Molière A, Lautrup S, et al. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging. 2022;14:6829–6839. DOI: 10.18632/aging.204248.
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186:243–278. DOI: 10.1016/j.cell.2022.11.001.
- Kroemer G, Maier AB, Cuervo AM, et al. From geroscience to precision geromedicine: Understanding and managing aging. Cell. 2025;188:2043–2062. DOI: 10.1016/j.cell.2025.03.011.
- Farr JN, Atkinson EJ, Achenbach SJ, et al. Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial. Nat Med. 2024;30(9):2605-2612. doi:10.1038/s41591-024-03096-2
- Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. doi:10.1056/NEJMoa1707914
- Wastyk HC, Fragiadakis GK, Perelman D, et al. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021;184(16):4137-4153.e14. doi:10.1016/j.cell.2021.06.019
- Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392-395. doi:10.1038/nature08221
- Waziry R, Ryan CP, Corcoran DL, et al. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nat Aging. 2023;3(3):248-257. doi:10.1038/s43587-022-00357-y
- Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA. 2014;311(23):2387-2396. doi:10.1001/jama.2014.5616
- Moqri M, Herzog C, Poganik JR, et al. Biomarkers of aging for the identification and evaluation of longevity interventions. Cell. 2023;186(18):3758-3775. doi:10.1016/j.cell.2023.08.003
Regulatory Disclaimer
Regulatory status
- No stem cell, cellular therapy, or exosome product is FDA-approved to slow aging or to treat age-related conditions.
- The medicines discussed in this article, including rapamycin, dasatinib, and canakinumab, are not FDA-approved to slow aging; their use for that purpose is investigational.
References to "stem cells" in this article describe research products and approaches studied elsewhere. The cellular therapy offered at Boulder Biologics uses cellular populations contained within autologous bone marrow–derived biologic material, not manufactured or expanded stem cell products.
This article is provided for educational purposes and is not a recommendation or medical advice.
Related patient explainers