Welcome to part 5 of ODX's "Biological Age Biomarkers" Series. In the fifth post, you'll learn about alkaline phosphatase's relationship with aging, why elevations in ALP are associated with all-cause mortality, and pathological conditions that can reduce longevity.
Alkaline phosphatase (ALP) represents a group of enzymes that function at an alkaline pH, primarily in the bone, liver, and kidneys (Yan 2023). These enzymes participate in protein phosphorylation, bone calcification and mineralization, cell growth, and cell apoptosis (Sharma 2014).
However, elevations in ALP are associated with all-cause mortality (Jia 2024) and pathological conditions that can reduce longevity, including coagulation (Yan 2023), inflammation, vascular calcification, endothelial dysfunction, cardiovascular disease, tissue fibrosis, and metabolic syndrome. Improved survival is associated with an ALP below 120 U/L (Haarhaus 2022).
A review of data from 34,147 adults participating in NHANES evaluations found that elevated ALP was significantly associated with all-cause and cardiovascular mortality. Subjects with an ALP above 82 U/L had more than twice the mortality rate of those an ALP of 55 U/L or below (Yan 2023).
ALP is critical in GABA metabolism, influences neuroplasticity and activity cortical functions, and is associated with neurodegenerative disease. In a cross-sectional study of 209 older adults, significantly higher ALP was also associated with subjective cognitive decline (SCD). Those with SCD had a mean ALP of 189.81 U/L, versus 164.52 in MCI and 139.91 in healthy controls (Boccardi 2021).
The increased alkaline phosphatase seen with brain injury and cerebrovascular dysfunction may be associated with neuronal loss and cognitive impairment. In the Oxford OPTIMA study, median serum ALP levels were higher in subjects with mild cognitive impairment and significantly higher in Alzheimer’s patients versus controls. Alkaline phosphatase inversely correlated with cognitive function even in control subjects. Alkaline phosphatase dephosphorylation of tau proteins can create a byproduct that promotes neuronal death, possibly linking elevated serum ALP with cognitive impairment (Kellett 2011).
In a retrospective study of 1,019 acute ischemic stroke patients, significantly higher ALP was associated with post-stroke cognitive impairment (PSCI). Mean ALP was 86.5 in those with PSCI vs. 68.6 U/L in those without PSCI. The risk of cognitive impairment increased by 42% for each 1 U/L increase in ALP (Jia 2020).
Postoperative cognitive dysfunction (POCD) following general anesthesia was also associated with significantly higher serum ALP 3 months post-op in a retrospective study of 1,593 subjects. Those with POCD had a mean ALP of 87.3 U/L versus 60.3 in those without POCD. Higher ALP correlated with higher hs-CRP as well (Li 2022).
Alkaline phosphatase (ALP) is incorporated into biomarker patterns used to evaluate biological age (Erema 2021, Levine 2013). As a biomarker of biological aging, ALP reflects an upstream process associated with age-related disease. ALP is also associated with multiorgan failure and is used in the clinical setting to predict mortality (Wu 2021).
In a large NHANES study, higher alkaline phosphatase was associated with increased mortality per 1000 person-years, especially for all-cause, cardiovascular, and cerebrovascular mortality (Yan 2023). Circulatory diseases, chronic disorders, and mortality risk are, in turn, associated with a higher biological age (Liu 2023).
Alkaline phosphate promotes bone mineralization but may have similar pathological effects in other tissues, including the brain. High levels of ALP have been observed in the arteriole vascular endothelium in the brain and heart, which may contribute to vascular aging and disease and increase cardio- and cerebrovascular risk and mortality (Hui 1998).
Boccardi, Virginia et al. “Serum alkaline phosphatase is elevated and inversely correlated with cognitive functions in subjective cognitive decline: results from the ReGAl 2.0 project.” Aging clinical and experimental research vol. 33,3 (2021): 603-609. doi:10.1007/s40520-020-01572-6
Erema, V. V., et al. "Biological Age Predictors: The Status Quo and Future Trends." *Int J Mol Sci.*, vol. 23, no. 23, 2022, doi:10.3390/ijms232315103.
Haarhaus, M., et al. "Alkaline Phosphatase: An Old Friend as Treatment Target for Cardiovascular and Mineral Bone Disorders in Chronic Kidney Disease." *Nutrients.*, vol. 14, no. 10, 2022, doi:10.3390/nu14102124.
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Jia, Qingqing et al. “A biological age model based on physical examination data to predict mortality in a Chinese population.” iScience vol. 27,3 108891. 3 Feb. 2024, doi:10.1016/j.isci.2024.108891
Kellett, Katherine Ab et al. “Plasma alkaline phosphatase is elevated in Alzheimer's disease and inversely correlates with cognitive function.” International journal of molecular epidemiology and genetics vol. 2,2 (2011): 114-21.
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Li, Xiaoli et al. “Elevated serum alkaline phosphatase correlates with postoperative cognitive dysfunction: A retrospective cohort study based on STROBE statement.” Medicine vol. 101,44 (2022): e31530. doi:10.1097/MD.0000000000031530
Liu, Wei-Shi et al. “Association of biological age with health outcomes and its modifiable factors.” Aging cell vol. 22,12 (2023): e13995. doi:10.1111/acel.13995
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Wu, Julia W et al. “Biological age in healthy elderly predicts aging-related diseases including dementia.” Scientific reports vol. 11,1 15929. 5 Aug. 2021, doi:10.1038/s41598-021-95425-5
Yan, Wei et al. “Associations of serum alkaline phosphatase level with all-cause and cardiovascular mortality in the general population.” Frontiers in endocrinology vol. 14 1217369. 5 Oct. 2023, doi:10.3389/fendo.2023.1217369