Biomarkers of aging for the identification and evaluation of longevity interventions

Moqri, Mahdi; Herzog, Chiara; Poganik, Jesse R.; Justice, Jamie; Belsky, Daniel W.; Higgins-Chen, Albert; Moskalev, Alexey; Fuellen, Georg; Cohen, Alan A.; Bautmans, Ivan; Widschwendter, Martin; Ding, Jingzhong; Fleming, Alexander; Mannick, Joan; Han, Jing-Dong Jackie; Zhavoronkov, Alex; Barzilai, Nir; Kaeberlein, Matt; Cummings, Steven; Kennedy, Brian K.; Ferrucci, Luigi; Horvath, Steve; Verdin, Eric; Maier, Andrea B.; Snyder, Michael P.; Sebastiano, Vittorio; Gladyshev, Vadim N.

doi:10.1016/j.cell.2023.08.003

Cited by 199 publications

(80 citation statements)

References 112 publications

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“…Overall, our findings suggest that newer epigenetic clocks such as DunedinPACE and GrimAge may have greater promise for gauging structural brain integrity relative to first-generation epigenetic clocks. This is in line with the growing consensus that aging biomarkers trained only on chronological age have limited ability to detect age-related health outcomes whereas aging biomarkers trained on the rate of biological aging are more associated with to age-related health outcomes (Morqri et al, 2023; Zhou et al, 2022).…”

Section: Discussionsupporting

confidence: 84%

A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts

Whitman,

Ryan,

Abraham

et al. 2023

Preprint

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Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3,380; total N individuals=2,322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, and thinner cortex. In two datasets, faster DunedinPACE was associated with greater burden of white matter hyperintensities. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.

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Section: Discussionsupporting

confidence: 84%

A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts

Whitman,

Ryan,

Abraham

et al. 2023

Preprint

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“…Information about deficit accumulation may motivate patients to engage in various health behaviors that prevent or decrease existing deficits (eg, smoking cessation or increasing physical activity). For example, eating nutritious foods or exercising regularly may affect multiple hallmarks of aging, reduce deficits, and improve aging-related outcomes . While the present study had a cross-sectional design, the results, especially the dose-response association between DAI and EAA, are consistent with a mechanistic association between deficit accumulation and biological aging.…”

Section: Discussionsupporting

confidence: 68%

Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer

Williams,

Mandelblatt,

Wang

et al. 2023

JAMA Netw Open

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ImportanceSurvivors of childhood cancer experience premature aging compared with community controls. The deficit accumulation index (DAI) uses readily available clinical data to measure physiological age in survivors; however, little data exist on how well deficit accumulation represents underlying biological aging among survivors of cancer.ObjectiveTo examine the associations between the DAI and epigenetic age acceleration (EAA) and mean leukocyte telomere length (LTL).Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the St Jude Lifetime Cohort, an assessment of survivors of childhood cancer who were treated at St Jude Children’s Research Hospital in Memphis, Tennessee. Data were collected between 2007 and 2016, assayed between 2014 and 2019, and analyzed between 2022 and 2023. Participants were adult survivors who were diagnosed between 1962 and 2012 and who survived 5 years or more from time of diagnosis. The analyses were restricted to survivors with European ancestry, as there were too few survivors with non-European ancestry.ExposuresThe DAI included 44 aging-related items, such as chronic health conditions and functional, psychosocial, and mental well-being. Item responses were summed and divided by the total number of items, resulting in a ratio ranging from 0 to 1. These DAI results were categorized based on reported associations with hospitalization and mortality: low, defined as a DAI less than 0.2; medium, defined as a DAI of 0.2 to less than 0.35; and high, defined as a DAI of 0.35 or higher.Main Outcomes and MeasuresGenome-wide DNA methylation was generated from peripheral blood mononuclear cell–derived DNA. The EAA was calculated as the residuals from regressing the Levine epigenetic age on chronological age. The mean LTL was estimated using whole-genome sequencing data.ResultsThis study included 2101 survivors of childhood cancer (1122 males [53.4%]; mean [SD] age, 33.9 [9.1] years; median [IQR] time since diagnosis, 25.1 [18.7-31.9] years) with European ancestry. Compared with survivors in the low DAI group, those in the high DAI group experienced 3.7 more years of EAA (β = 3.66; 95% CI, 2.47-4.85; P &lt; .001), whereas those in the medium DAI group experienced 1.8 more years of EAA (β = 1.77; 95% CI, 0.84-2.69; P &lt; .001), independent of treatment exposures. The EAA and DAI association was consistent across 3 common diagnoses (acute lymphoblastic leukemia, Hodgkin lymphoma, and central nervous system tumors) and across chronological age groups. For example, among acute lymphoblastic leukemia survivors, those in the medium DAI group (β = 2.27; 95% CI, 0.78-3.76; P = .001) experienced greater EAA vs those in the low DAI group. Similarly, among survivors younger than 30 years, the high DAI group experienced 4.9 more years of EAA vs the low DAI group (β = 4.95; 95% CI, 2.14-7.75; P &lt; .001). There were no associations between mean LTL residual and the DAI.Conclusions and RelevanceThis cross-sectional study of survivors of childhood cancer showed that the DAI was associated with EAA, suggesting an underlying biological process to the accumulation of deficits. Both the DAI and EAA were effective at identifying aging phenotypes, and either may be used to measure aging and response to interventions targeting aging pathways.

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“…aging conso rtium. org/ ), and other entities to develop feasible, valid, and, in the context of interventions targeting specific hallmarks, modifiable biomarkers of aging (Moqri et al, 2023(Moqri et al, , 2024Rutledge et al, 2022). As an example, we exploited the literature and the secretome of several human cell types induced to senescence in vitro to develop a candidate panel of senescence biomarkers, comprised of cytokines, chemokines, matrix remodeling proteins, growth factors, and other proteins, that could be reliably measured in the blood of humans (Schafer et al, 2020).…”

Section: E D I T O R I a L Hungry For Biomarkers Of Agingmentioning

confidence: 99%

Hungry for biomarkers of aging

LeBrasseur

2024

Aging Cell

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Biomarkers of aging for the identification and evaluation of longevity interventions

Cited by 199 publications

References 112 publications

A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts

A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts

Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer

Hungry for biomarkers of aging

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