Molecular and physiological manifestations and measurement of aging in humans
Open accessAbstract
Summary: Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs. This reduction manifests as a decreased physiological reserve in response to stress (termed homeostenosis) and a time‐dependent failure of complex molecular mechanisms that cumulatively create disorder. Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators. Individuals with the same chronological age exhibit differential trajectories of age‐related decline, and it follows that we should assess biological age distinctly from chronological age. In this review, we outline mechanisms of aging with attention to well‐described molecular and cellular hallmarks and discuss physiological changes of aging at the organ‐system level. We suggest methods to measure aging with attention to both molecular biology (e.g., telomere length and epigenetic marks) and physiological function (e.g., lung function and echocardiographic measurements). Finally, we propose a framework to integrate these molecular and physiological data into a composite score that measures biological aging in humans. Understanding the molecular and physiological phenomena that drive the complex and multifactorial processes underlying the variable pace of biological aging in humans will inform how researchers assess and investigate health and disease over the life course. This composite biological age score could be of use to researchers seeking to characterize normal, accelerated, and exceptionally successful aging as well as to assess the effect of interventions aimed at modulating human aging.
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Written from the paper’s full text.
TL;DR
This review synthesizes molecular hallmarks and organ-level physiological changes of human aging and proposes a composite biological age score (BAS) integrating molecular biomarkers with physiological measures. It argues that biological age should be assessed distinctly from chronological age and outlines a framework for derivation and validation in longitudinal cohorts.
Key findings
- The review frames aging around nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
- Genetics accounts for only 20–30% of lifespan variability in human twin and founder population family studies, though heritable factors may contribute more at extreme ages.
- Organ-level declines include FVC falling 0.15–0.30 L per decade in nonsmoking men, FEV1 falling 0.20–0.30 L/s per decade, peak aerobic capacity declining more than 20% per decade after age 70, creatinine clearance falling 7.5–10 mL per decade, glomerulosclerosis up to 30% by age 75, liver mass decreasing 20–40%, and atrial pacemaker cellular loss of 50–75% by age 50.
- The proposed BAS would combine molecular markers such as telomere length and epigenetic marks with physiological measures such as FEV1 and echocardiographic e’ velocity, using modeling approaches including multiple linear regression, principal component analysis, and Klemera and Doubal’s method; an NHANES-based biological age measure cited had more than 9000 participants aged 30–75 years at baseline.
Methods
- Narrative review; findings were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using the search terms “aging,” “measurement,” and “assessment,” with English articles published between 1980 and 2016 included except for historical interest.
- No primary data collection or meta-analysis; the paper discusses molecular and physiological aging mechanisms, presents tables of candidate biomarkers and organ-specific measures, and proposes a conceptual composite BAS framework.
- The paper suggests derivation and validation of a BAS in population-based datasets and longitudinal epidemiologic cohorts, with head-to-head comparisons of mathematical modeling methods.
Limitations
- Stated: existing biological age scores have limitations including small sample sizes, limited testing of variables, omission of novel molecular markers, lack of participant-level longitudinal follow-up with repeated measures, and a dearth of population-level replication and validation in clinical settings.
- Stated: centenarians are rare, making meaningful sample sizes difficult; longevity and healthy aging may not be synonymous; and lifespan as a phenotype is costly and time-consuming to study.
- Evident: as a review, the paper provides no new empirical validation; the BAS is conceptual, the depicted aging trajectories are hypothetical, and the trajectory of biological aging is not known.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Premisecitation
Heritable factors may represent a significantly larger contribution to lifespan at extreme ages.
“However, heritable factors may represent a significantly larger contribution to lifespan at extreme ages, and the exceptionally aged may offer an opportunity to find rare genetic variants associated with longevity (Tan et al., 2010; Sebastiani et al., 2012).”
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- cites Sebastiani et al., 2012
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- Premisecitation
The heritable contribution to aging is limited for most humans, with genetics accounting for only 20-30% of lifespan variability in human twin and founder population family studies.
“The heritable contribution to aging is limited for most humans, with genetics accounting for only 20–30% of lifespan variability in human twin and founder population family studies (Mitchell et al., 2001; Kenyon, 2010).”
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- cites Kenyon, 2010
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- Interpretationreasoning
No single factor or molecular mechanism explains progressive age-related homeostenosis.
“Regardless, no single factor or molecular mechanism explains progressive age‐related homeostenosis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Chronological age offers limited information regarding the complex processes driving biological aging.
“Chronological age offers limited information regarding the complex processes driving biological aging.”
Quote in the paperSubstantial claim- Rests on an assumption: Individuals with the same chronological age and their organs exhibit differential trajectories of age-related decline.
- Interpretationnone given
Lung function represents one of the few consistently reliable physiological markers of aging.
“Lung function represents one of the few consistently reliable physiological markers of aging.”
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- Premisecitation
The aging cardiovascular system displays decreased compliance of the aorta and large vessels.
“The aging cardiovascular system displays decreased compliance of the aorta and large vessels (Vaitkevicius et al., 1993).”
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- Premisecitation
The autophagy-lysosomal system and the ubiquitin-proteasome system become hypofunctional with aging.
“The two key proteolytic pathways responsible for protein quality control—the autophagy–lysosomal system and the ubiquitin–proteasome system—become hypofunctional with aging (Calamini et al., 2012; Tomaru et al., 2012).”
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- Premisecitation
Telomerase overexpression increases median lifespan in mice.
“Accordingly, telomerase overexpression increases median lifespan in mice (Bernardes de Jesus et al., 2012).”
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- Premisecitation
Centenarians exemplify an exceptional survival phenotype who delay disability and disease until an average age of 93 years.
“Centenarians exemplify an exceptional survival phenotype who delay disability and disease until an average age of 93 years (Andersen et al., 2012).”
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- Interpretationreasoning
While much research has focused on quantification of biological aging, a comprehensive and integrative score incorporating molecular biomarkers and physiological functional parameters is lacking.
“While much research has focused on quantification of biological aging, a comprehensive and integrative score incorporating molecular biomarkers and physiological functional parameters is lacking.”
Quote in the paperSubstantial claim - Premisecitation
Mice fed the mTOR inhibitor rapamycin in late life experienced extension of median and maximal lifespan.
“Strikingly, mice fed the mTOR inhibitor rapamycin in late life experienced extension of median and maximal lifespan, supporting a role for mTOR signaling and pharmacologic inhibition in lifespan regulation (Harrison et al., 2009).”
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- Premisecitation
The insulin and insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway represents an extremely well-conserved pro-aging pathway.
“In addition, the insulin and insulin‐like growth factor 1 (IGF‐1) signaling (IIS) pathway, which targets the FOXO transcription factors and mTOR complexes, represents an extremely well‐conserved pro‐aging pathway (Kenyon, 2010; Barzilai et al., 2012).”
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Mouse and human data implicate genomic instability in accelerated aging.
“Mouse and human data implicate genomic instability in accelerated aging (Burtner & Kennedy, 2010) with myriad exogenous agents (e.g., radiation and xenobiotic compounds) as well as endogenous processes (e.g., DNA replication errors and reactive oxygen species [ROS]) causing damage to DNA (Hoeijmakers, 2009).”
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- Premisecitation
Mitochondrial dysfunction in the form of decreased respiratory chain efficiency, resulting electron leak, and diminished ATP production may contribute to senescence.
“Mitochondrial dysfunction in the form of decreased respiratory chain efficiency, resulting electron leak, and diminished ATP production may contribute to senescence (Green et al., 2011).”
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- Premisecitation
Protein levels of p16INK4a and p19ARF correlate with chronological age remarkably well in humans and model organisms with a large difference (up to an order of magnitude) comparing young and old tissues.
“As a biomarker, protein levels of p16INK4a and p19ARF correlate with chronological age remarkably well in humans and model organisms with a large difference (up to an order of magnitude) comparing young and old tissues (Krishnamurthy et al., 2004; Ressler et al., 2006).”
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Large-scale genomewide DNA methylation-based epigenetic analyses have identified an epigenetic clock that is closely correlated with healthy aging.
“Large‐scale genomewide DNA methylation‐based epigenetic analyses using a variety of cell types and tissues have identified an ‘epigenetic clock’ that is closely correlated with healthy aging (Horvath, 2013).”
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- Premisecitation
With aging, there exists a propensity for stable cell cycle arrest known as cellular senescence.
“With aging, there exists a propensity for stable cell cycle arrest known as cellular senescence (Hayflick & Moorhead, 1961; Collado et al., 2007).”
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- Premisecitation
A significant body of data supports ROS as a cause of accelerated aging.
“A significant body of data supports ROS as a cause of accelerated aging (Harman, 1965).”
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- Classified as probably not a substantial claim. 8
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Interpretationnone givenThe aging immune system displays progressive changes collectively described as immunosenescence; these changes result in increased susceptibility to infection, malignancy, and autoimmunity.
“The aging immune system displays progressive changes collectively described as immunosenescence; these changes result in increased susceptibility to infection, malignancy, and autoimmunity.”
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PremisecitationMost mammalian somatic cells lack telomerase, which results in replication-dependent sequence loss at chromosomal ends, often leading to replicative senescence.
“Most mammalian somatic cells lack telomerase—a specialized DNA polymerase responsible for repairing telomeres after cell division—which results in replication‐dependent sequence loss at chromosomal ends, often leading to replicative senescence (the Hayflick limit) (Hayflick & Moorhead, 1961; Jiang et al., 2008).”
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PremisecitationPhysiological aging involves a progressive detrimental change in maximal organ function with differential trajectories across organ systems.
“Physiological aging involves a progressive detrimental change in maximal organ function with differential trajectories across organ systems (Fig. 3) (Shock, 1956).”
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PremisecitationLópez-Otín and colleagues proposed nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
“López‐Otín and colleagues proposed nine so‐called hallmarks of aging—genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication—that frame mechanisms underlying senescence (Lopez‐Otin et al., 2013).”
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PremisecitationForced vital capacity (FVC) declines 0.15-0.30 L per decade in nonsmoking men, and the forced expiratory volume in one-second (FEV1) falls 0.20-0.30 L/s per decade with a steeper decline in the 7th and 8th decades.
“Forced vital capacity (FVC) declines 0.15‐0.30 L per decade in nonsmoking men, and the forced expiratory volume in one‐second (FEV1) falls 0.20–0.30 L/s per decade with a steeper decline in the 7th and 8th decades (Xu et al., 1995).”
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PremisecitationMetastatic aging-in which aging in one tissue accelerates aging in other tissues-may occur via gap junctions and ROS signaling and via miRNAs secreted into the blood that promote senescence in remote tissues.
“Metastatic aging—in which aging in one tissue accelerates aging in other tissues (Lavasani et al., 2012)—may occur via gap junctions and ROS signaling and via miRNAs secreted into the blood that promote senescence in remote tissues (Grillari & Grillari‐Voglauer, 2010; Nelson et al., 2012).”
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PremisecitationLongitudinal research efforts such as the United States Precision Medicine Initiative and the European MARK-AGE Consortium are seeking to define a set of human aging biomarkers.
“longitudinal research efforts such as the United States Precision Medicine Initiative seeking to enroll 1 million participants and the European MARK‐AGE Consortium with 3200 enrolled participants are seeking to define a set of human aging biomarkers (Burkle et al., 2015)”
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PremisecitationEpigenetic alterations occur with aging and impact cellular function.
“Epigenetic alterations—heritable changes in phenotype that are independent of DNA sequence mutations—occur with aging and impact cellular function (Sen et al., 2016).”
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PremisecitationTelomeres shorten and become increasingly susceptible to damage with age.
“Telomeres, the chromatin tips responsible for preventing degradation at chromosomal ends, shorten and become increasingly susceptible to damage with age (Blackburn et al., 2006).”
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Study design and conductnone givenWith exceptions for historical interest, only articles published in English between 1980 and 2016 were included.
“With exceptions for historical interest, only articles published in English between 1980 and 2016 were included.”
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InterpretationreasoningBiological plausibility suggests that no single biomarker is likely to suffice given the underlying multisystem nature of the aging process with changes occurring on a molecular and organ-based level underscoring the utility of an aggregate score of biological aging.
“Further, biological plausibility suggests that no single biomarker is likely to suffice given the underlying multisystem nature of the aging process with changes occurring on a molecular and organ‐based level underscoring the utility of an aggregate score of biological aging.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningRedundancies in selected aging parameters may exist.
“redundancies in selected aging parameters may exist”
Quote in the paperSubstantial claim- Rests on an assumption: Aging is a systemic process composed of interdependent processes.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFindings for this review were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using the search terms aging, measurement, and assessment.
“Findings for this review were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using the search terms ‘aging’, ‘measurement’, and ‘assessment’.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
PremisecitationAging cannot be escaped.
“While aging cannot be escaped (Gompertz, 1825)”
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PremisecitationThe kidneys develop a diffuse glomerulosclerosis with age (up to 30% by age 75); remaining glomeruli display impaired filtering ability.
“The kidneys develop a diffuse glomerulosclerosis with age (up to 30% by age 75) (Nyengaard & Bendtsen, 1992); remaining glomeruli display impaired filtering ability.”
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PremisecitationIn vivo evidence of the causal role telomerase plays in aging remains controversial, as telomerase knockout mice demonstrate no overt phenotype and reduced longevity only after multiple generations.
“However, in vivo evidence of the causal role telomerase plays in aging remains controversial, as telomerase knockout mice demonstrate no overt phenotype and reduced longevity only after multiple generations (Rudolph et al., 1999).”
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InterpretationreasoningCognitive decline with aging is multifactorial and related to changes in structure as well as synaptic plasticity.
“Cognitive decline with aging is multifactorial and related to changes in structure as well as synaptic plasticity.”
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PremisecitationAnabolic signaling causes accelerated aging and caloric restriction extends lifespan in murine and nonhuman primate models.
“Deregulated nutrient sensing represents an important and potentially druggable hallmark of aging, as anabolic signaling causes accelerated aging and caloric restriction extends lifespan in murine and nonhuman primate models (Colman et al., 2014; López‐Otín et al., 2016; Vermeij et al., 2016).”
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- cites López‐Otín et al., 2016
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InterpretationreasoningSeveral limitations of existing scores impede current investigations, including small sample sizes, limited testing of variables, omission of novel molecular markers, lack of participant-level longitudinal follow-up with repeated measures in the same individual, and dearth of population-level replication and validation in clinical settings for predictive ability.
“Several limitations of existing scores impede current investigations, including small sample sizes, limited testing of variables, omission of novel molecular markers, lack of participant‐level longitudinal follow‐up with repeated measures in the same individual, and dearth of population‐level replication and validation in clinical settings for predictive ability.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe derivation cohort for the NHANES-based measure of biological age contained more than 9000 participants aged 30-75 years at baseline and integrated physiological and biochemical markers at a single time point.
“The derivation cohort for the NHANES‐based measure of biological age contained more than 9000 participants aged 30–75 years at baseline and integrated physiological and biochemical markers at a single time point (Levine, 2013).”
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PremisecitationSenescent cells display a characteristic secretory profile-the senescence-associated secretory phenotype-that contributes to low-level systemic inflammation (inflammaging) and likely facilitates the spread of pro-senescence signals through tissues and systemically alters the extracellular matrix.
“Senescent cells display a characteristic secretory profile—the senescence‐associated secretory phenotype—that contributes to low‐level systemic inflammation (so‐called inflammaging) and likely facilitates the spread of pro‐senescence signals through tissues and systemically alters the extracellular matrix in parallel (Kuilman et al., 2010).”
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PremisecitationProtein homeostasis (proteostasis) becomes impaired with aging and enhanced proteostasis can maintain the integrity of the proteome and delay mammalian senescence.
“Protein homeostasis (proteostasis) becomes impaired with aging and enhanced proteostasis can maintain the integrity of the proteome and delay mammalian senescence (Zhang & Cuervo, 2008; Koga et al., 2011).”
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PremisecitationRandomized clinical trials are being discussed and planned with the intention of testing the therapeutic benefit of drugs such as metformin on human aging.
“randomized clinical trials are being discussed and planned with the intention of testing the therapeutic benefit of drugs such as metformin on human aging (Albert Einstein College of Medicine of Yeshiva University 2015; Longo et al., 2015)”
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InterpretationreasoningAging affects all organ systems and must be assessed through a variety of physiological measures, as aging varies greatly organ-to-organ and person-to-person and results in impaired reserve capacity and limited ability to respond to stress.
“Aging affects all organ systems and must be assessed through a variety of physiological measures, as aging varies greatly organ‐to‐organ and person‐to‐person and results in impaired reserve capacity and limited ability to respond to stress.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs.
“Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs.”
The paper relies on this without support.
Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators.
“Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators (Fig. 1).”
The paper relies on this without support.
Individuals with the same chronological age and their organs exhibit differential trajectories of age-related decline.
“Individuals with the same chronological age and their organs exhibit differential trajectories of age‐related decline, and it follows that we should assess biological age distinctly from chronological age.”
The authors state this as an assumption.
The trajectory of biological aging is not known.
“The aging lines are depicted hypothetically as straight lines, but the trajectory of biological aging is not known.”
The paper relies on this without support.
Aging is a systemic process composed of interdependent processes.
“given that aging is a systemic process composed of interdependent processes”
The paper relies on this without support.
Postponing senescent changes and disease onset offers the potential to extend fitness, vitality, and years lived free of morbidity and frailty.
“postponing senescent changes and disease onset offers the potential to extend fitness, vitality, and years lived free of morbidity and frailty”
The paper relies on this without support.
There is evidence for modulation of lifespan in preclinical models and animal species via genetic and pharmacologic interventions.
“While there is evidence for modulation of lifespan in preclinical models and animal species via genetic and pharmacologic interventions”
The paper relies on this without support.
Conclusive methods to measure biological age remain debatable.
“While conclusive methods to measure biological age remain debatable”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
At the level of an individual, a rate of aging can be determined by the rate of change of virtually any anatomic structure or physiological process.
“At the level of an individual, a rate of aging can be determined by the rate of change of virtually any anatomic structure or physiological process (e.g., bone density, renal function, etc., for humans), as there are almost no aspects of anatomy or physiology that do not exhibit declines as an individual ages.23”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [23]
Almost no aspects of anatomy or physiology do not exhibit declines as an individual ages.
“as there are almost no aspects of anatomy or physiology that do not exhibit declines as an individual ages.23”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [23]
The decline of tissue function is commonly illustrated as gradual and steady, perhaps with a more rapid decline toward the end of life.
“In general, the decline of tissue function is commonly illustrated as gradual and steady,23 perhaps with a more rapid decline toward the end of life.”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [23]
In humans, the cardiovascular system exhibits a much greater functional decline with age than the gastrointestinal system, at least based on physiological parameters measured on absolute scales.
“For example, in humans the cardiovascular system exhibits a much greater functional decline with age than the gastrointestinal system,23 at least based on physiological parameters measured, as noted above, on absolute scales.”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [23]
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- Authors
- Khan, S. S., Singer, B. D., & Vaughan, D. E.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Vaughan, Douglas E.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2017-05-23
- Volume
- 16
- Issue
- 4
- Pages
- 624-633
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC5506433
- OpenAlex
- W2617171469
- Cited by
- 530
- References
- 133
- Citations by year
- 2026: 56 · 2025: 66 · 2024: 75 · 2023: 61 · 2022: 78 · 2021: 74 · 2020: 50 · 2019: 40 · 2018: 26 · 2017: 3 · 2012: 1
- FWCI
- 3.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01 HL51387, K08 HL128867, F32 HL129695)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Social Sciences › Psychology › Neuropsychology and Physiological Psychology › Aging and Gerontology Research
- Keywords
- biological aging, biological age, telomere length, lung function, echocardiographic measurement, accelerated aging, successful aging, age-related decline, physiological reserve
- MeSH terms
- Aging, Heart Function Tests, Humans, Kidney Function Tests, Metformin, Organ Specificity, Respiratory Function Tests, Biomarkers, Cytokines, Cellular Senescence, Epigenesis, Genetic, Telomere Homeostasis, Gene-Environment Interaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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