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Anti-retroviral therapy (ART) has successfully extended the life expectancy of HIV-infected persons to close to that of ordinary people [1].
However, the quality of life of these HIV-infected people whose life expectancy has been extended after treatment is not good.
They are often more susceptible to cardiovascular disease, cancer, cognitive impairment, and osteoporosis, which are common in the elderly [2,3].
In other words, HIV-infected people may be older than ordinary people (professional speaking: their biological age is greater than their actual age), even if they receive ART to achieve virological suppression, they will still have these problems, which may be caused by HIV infection Immune aging and inflammation, and the effect of ART intervention on it is rarely reported.
For the acceleration of aging, there is a lack of reliable biomarkers to predict.
For a long time, telomere length has been considered to be related to cell aging, and cell aging is closely related to individual aging, but in fact it is not accurate to predict individual lifespan by telomere length [4].
Currently considered to be the most reliable predictor of the degree of aging (biological age) of an individual is the so-called "epigenetic clock" [5].
Recently, a research team led by Jose R Arribas, director of the Department of Infectious Diseases of La Paz Hospital in Spain, published important research results in the journal The Lancet-HIV.
They used the epigenetic clock tool to find that the rate of aging of HIV-infected patients Significantly faster than ordinary people, ART can partially delay the acceleration of aging caused by HIV infection 2 years after the beginning of ART [6].
This result indicates that ART reduces the risk of “senile disease” in infected patients through epigenetic effects in the early stage of treatment, thereby extending their life expectancy.
This is the first study to evaluate post-ART epigenetic aging biomarkers in HIV-infected patients participating in clinical trials.
Screenshot of the paper Epigenetics is a method of inheritance that does not involve changes in DNA sequence, including DNA methylation, chromatin modification, and non-coding RNA regulation (that is, epigenome).
In recent years, scientists have discovered that changes in the epigenome are related to aging.
The epigenetic clock is based on the DNA methylation level of CpG dinucleotide sites that changes with age to predict the epigenetic age of an individual.
This represents biological age.
The acceleration of senescence in epigenetics (ie, the epigenetic age is greater than the actual age, EAA) is related to the incidence and death of "senile diseases" [7].
This is why some people look older than their peers when their living habits are similar, and their physical fitness is not as good as their age.
Closer to home, the work done by the Jose R Arribas team is a sub-study of NEAT001, and all HIV-infected persons in the group come from NEAT001.
The researchers randomly selected 201 infected patients and excluded those who lacked blood samples before and after treatment and did not meet the quality control requirements of methylation analysis.
Finally, a total of 168 cases were included in the final analysis, and an additional 44 age- and gender-matched individuals were recruited.
Ordinary people who were not infected with HIV served as controls.
The next methylation analysis is more routine.
First, extract DNA from the whole blood samples of all participants, and then treat them with bisulfite.
Unmethylated cytosine is converted into uracil, methylated cytosine No change, then use the methylation chip for high-throughput detection of methylation level.
After obtaining the methylation expression profiles of all samples, the researchers used four different tools based on the epigenetic clock to estimate their epigenetic age and found that it had a strong correlation with the actual age.
Four The correlations predicted by these tools are 0.
9, 0.
92, 0.
87, and 0.
82, respectively.
Whether it is HIV-infected people (A) or ordinary people (B) before and after treatment, the epigenetic age based on the four epigenetic clocks has a strong correlation with the actual age.
It is similar to that of uninfected ordinary people.
In contrast, HIV-infected individuals have a higher epigenetic age before treatment, and the four tool predictions are 2.
5, 1.
4, 2.
8, and 7.
3 years higher, respectively. Compared with before treatment, the epigenetic age of HIV-infected patients has decreased after treatment, and the four tool predictions have decreased by 1.
1, 1.
6, 0.
6, and 3.
6 years, respectively.
However, from the prediction results of two more clinically significant tools (GrimAge and PhenoAge), the epigenetic age of HIV-infected patients after treatment is still greater than that of ordinary people.
Therefore, ART may partially delay the acceleration of aging caused by HIV infection, and has nothing to do with the treatment plan.
The epigenetic age difference of HIV-infected patients before and after treatment (red and light red) and ordinary people (pink) Since HIV infection accelerates aging, will more serious infections lead to faster aging? Data show that compared with other infected people, those infected with less than 200 CD4 cells/ul or with a viral load of more than 100,000 copies/ml age faster.
However, only those infected with less than 200 CD4 cells/ul had a greater decline in their epigenetic age after treatment.
The epigenetic ageing rate of infected persons with less than 200 CD4 cells/ul (A red) and viral load exceeding 100,000 copies/ml (B green) is significantly faster than other infected persons.
In addition, consistent with the expectations of researchers, In the process of ART intervention, the immune system function of the infected person is restored, and the white blood cell composition in their body changes to poorly differentiated T cells and fewer pro-inflammatory white blood cells.
In general, the epigenetic clock based on DNA methylation can estimate the biological age of an individual based on the methylation patterns of some CpG dinucleotide sites on the genome.
Risks are closely related, so theoretically speaking, by comparing actual age with biological age, we can predict the life expectancy of an individual.
This study found that compared with ordinary people, HIV-infected people still have EAA after treatment, indicating that the acceleration of aging caused by HIV infection before the treatment takes effect may be irreversible, and the risk of “senile disease” associated with it is irreversibly irreversible.
Elevated.
Previous studies have found that people with cognitive impairment associated with HIV infection have higher EAA [8].
There are even studies that have found that when the age and the number of CD4 cells match, the same HIV-infected people with weaker physiques are even 10 years older in terms of epigenetic age [9].
In this study, short-term ART showed a partial reversal effect on EAA.
In the future, further evaluation of the long-term effect is needed, and it is still unknown whether there is a therapy that can completely reverse EAA.
At the same time, the clinical correlation between EAA and other symptoms may also become the basis for preventing other complications of HIV-infected patients.
References: [1] Marcus JL, Leyden WA, Alexeeff SE, et al.
Comparison of Overall and Comorbidity-Free Life Expectancy Between Insured Adults With and Without HIV Infection, 2000-2016.
JAMA Netw Open.
2020;3(6) :e207954.
Published 2020 Jun 1.
doi:10.
1001/jamanetworkopen.
2020.
7954[2] Guaraldi G, Orlando G, Zona S, et al.
Premature age-related comorbidities among HIV-infected persons compared with the general population.
Clin Infect Dis.
2011;53(11):1120-1126.
doi:10.
1093/cid/cir627[3] Kaplan-Lewis E, Aberg JA, Lee M.
Aging with HIV in the ART era.
Semin Diagn Pathol.
2017;34(4) :384-397.
doi:10.
1053/j.
semdp.
2017.
04.
002[4] Mather KA, Jorm AF, Parslow RA, Christensen H.
Is telomere length a biomarker of aging? A review.
J Gerontol A Biol Sci Med Sci.
2011;66(2):202-213.
doi:10.
1093/gerona/glq180[5] Horvath S, Raj K.
DNA methylation-based biomarkers and the epigenetic clock theory of ageing.
Nat Rev Genet.
2018;19(6):371-384.
doi:10.
1038/s41576-018-0004-3[6] Esteban-Cantos A, Rodríguez-Centeno J, Barruz P, et al.
Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial.
Lancet HIV.
2021;8(4):e197-e205.
doi:10.
1016 /S2352-3018(21)00006-0[7] Ryan CP.
"Epigenetic clocks": Theory and applications in human biology [published online ahead of print, 2020 Aug 26].
Am J Hum Biol.
2020;e23488.
doi: 10.
1002/ajhb.
23488[8] Levine AJ, Quach A, Moore DJ, et al.
Accelerated epigenetic aging in brain is associated with pre-mortem HIV-associated neurocognitive disorders.
J Neurovirol.
2016;22(3):366-375 .
doi:10.
1007/s13365-015-0406-3[9] Sánchez-Conde M, Rodriguez-Centeno J,Dronda F, et al.
Frailty phenotype: a clinical marker of age acceleration in the older HIV-infected population.
Epigenomics.
2019;11(5):501-509.
doi:10.
2217/epi-2018-0130 Edit | Ying Yuyan
However, the quality of life of these HIV-infected people whose life expectancy has been extended after treatment is not good.
They are often more susceptible to cardiovascular disease, cancer, cognitive impairment, and osteoporosis, which are common in the elderly [2,3].
In other words, HIV-infected people may be older than ordinary people (professional speaking: their biological age is greater than their actual age), even if they receive ART to achieve virological suppression, they will still have these problems, which may be caused by HIV infection Immune aging and inflammation, and the effect of ART intervention on it is rarely reported.
For the acceleration of aging, there is a lack of reliable biomarkers to predict.
For a long time, telomere length has been considered to be related to cell aging, and cell aging is closely related to individual aging, but in fact it is not accurate to predict individual lifespan by telomere length [4].
Currently considered to be the most reliable predictor of the degree of aging (biological age) of an individual is the so-called "epigenetic clock" [5].
Recently, a research team led by Jose R Arribas, director of the Department of Infectious Diseases of La Paz Hospital in Spain, published important research results in the journal The Lancet-HIV.
They used the epigenetic clock tool to find that the rate of aging of HIV-infected patients Significantly faster than ordinary people, ART can partially delay the acceleration of aging caused by HIV infection 2 years after the beginning of ART [6].
This result indicates that ART reduces the risk of “senile disease” in infected patients through epigenetic effects in the early stage of treatment, thereby extending their life expectancy.
This is the first study to evaluate post-ART epigenetic aging biomarkers in HIV-infected patients participating in clinical trials.
Screenshot of the paper Epigenetics is a method of inheritance that does not involve changes in DNA sequence, including DNA methylation, chromatin modification, and non-coding RNA regulation (that is, epigenome).
In recent years, scientists have discovered that changes in the epigenome are related to aging.
The epigenetic clock is based on the DNA methylation level of CpG dinucleotide sites that changes with age to predict the epigenetic age of an individual.
This represents biological age.
The acceleration of senescence in epigenetics (ie, the epigenetic age is greater than the actual age, EAA) is related to the incidence and death of "senile diseases" [7].
This is why some people look older than their peers when their living habits are similar, and their physical fitness is not as good as their age.
Closer to home, the work done by the Jose R Arribas team is a sub-study of NEAT001, and all HIV-infected persons in the group come from NEAT001.
The researchers randomly selected 201 infected patients and excluded those who lacked blood samples before and after treatment and did not meet the quality control requirements of methylation analysis.
Finally, a total of 168 cases were included in the final analysis, and an additional 44 age- and gender-matched individuals were recruited.
Ordinary people who were not infected with HIV served as controls.
The next methylation analysis is more routine.
First, extract DNA from the whole blood samples of all participants, and then treat them with bisulfite.
Unmethylated cytosine is converted into uracil, methylated cytosine No change, then use the methylation chip for high-throughput detection of methylation level.
After obtaining the methylation expression profiles of all samples, the researchers used four different tools based on the epigenetic clock to estimate their epigenetic age and found that it had a strong correlation with the actual age.
Four The correlations predicted by these tools are 0.
9, 0.
92, 0.
87, and 0.
82, respectively.
Whether it is HIV-infected people (A) or ordinary people (B) before and after treatment, the epigenetic age based on the four epigenetic clocks has a strong correlation with the actual age.
It is similar to that of uninfected ordinary people.
In contrast, HIV-infected individuals have a higher epigenetic age before treatment, and the four tool predictions are 2.
5, 1.
4, 2.
8, and 7.
3 years higher, respectively. Compared with before treatment, the epigenetic age of HIV-infected patients has decreased after treatment, and the four tool predictions have decreased by 1.
1, 1.
6, 0.
6, and 3.
6 years, respectively.
However, from the prediction results of two more clinically significant tools (GrimAge and PhenoAge), the epigenetic age of HIV-infected patients after treatment is still greater than that of ordinary people.
Therefore, ART may partially delay the acceleration of aging caused by HIV infection, and has nothing to do with the treatment plan.
The epigenetic age difference of HIV-infected patients before and after treatment (red and light red) and ordinary people (pink) Since HIV infection accelerates aging, will more serious infections lead to faster aging? Data show that compared with other infected people, those infected with less than 200 CD4 cells/ul or with a viral load of more than 100,000 copies/ml age faster.
However, only those infected with less than 200 CD4 cells/ul had a greater decline in their epigenetic age after treatment.
The epigenetic ageing rate of infected persons with less than 200 CD4 cells/ul (A red) and viral load exceeding 100,000 copies/ml (B green) is significantly faster than other infected persons.
In addition, consistent with the expectations of researchers, In the process of ART intervention, the immune system function of the infected person is restored, and the white blood cell composition in their body changes to poorly differentiated T cells and fewer pro-inflammatory white blood cells.
In general, the epigenetic clock based on DNA methylation can estimate the biological age of an individual based on the methylation patterns of some CpG dinucleotide sites on the genome.
Risks are closely related, so theoretically speaking, by comparing actual age with biological age, we can predict the life expectancy of an individual.
This study found that compared with ordinary people, HIV-infected people still have EAA after treatment, indicating that the acceleration of aging caused by HIV infection before the treatment takes effect may be irreversible, and the risk of “senile disease” associated with it is irreversibly irreversible.
Elevated.
Previous studies have found that people with cognitive impairment associated with HIV infection have higher EAA [8].
There are even studies that have found that when the age and the number of CD4 cells match, the same HIV-infected people with weaker physiques are even 10 years older in terms of epigenetic age [9].
In this study, short-term ART showed a partial reversal effect on EAA.
In the future, further evaluation of the long-term effect is needed, and it is still unknown whether there is a therapy that can completely reverse EAA.
At the same time, the clinical correlation between EAA and other symptoms may also become the basis for preventing other complications of HIV-infected patients.
References: [1] Marcus JL, Leyden WA, Alexeeff SE, et al.
Comparison of Overall and Comorbidity-Free Life Expectancy Between Insured Adults With and Without HIV Infection, 2000-2016.
JAMA Netw Open.
2020;3(6) :e207954.
Published 2020 Jun 1.
doi:10.
1001/jamanetworkopen.
2020.
7954[2] Guaraldi G, Orlando G, Zona S, et al.
Premature age-related comorbidities among HIV-infected persons compared with the general population.
Clin Infect Dis.
2011;53(11):1120-1126.
doi:10.
1093/cid/cir627[3] Kaplan-Lewis E, Aberg JA, Lee M.
Aging with HIV in the ART era.
Semin Diagn Pathol.
2017;34(4) :384-397.
doi:10.
1053/j.
semdp.
2017.
04.
002[4] Mather KA, Jorm AF, Parslow RA, Christensen H.
Is telomere length a biomarker of aging? A review.
J Gerontol A Biol Sci Med Sci.
2011;66(2):202-213.
doi:10.
1093/gerona/glq180[5] Horvath S, Raj K.
DNA methylation-based biomarkers and the epigenetic clock theory of ageing.
Nat Rev Genet.
2018;19(6):371-384.
doi:10.
1038/s41576-018-0004-3[6] Esteban-Cantos A, Rodríguez-Centeno J, Barruz P, et al.
Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial.
Lancet HIV.
2021;8(4):e197-e205.
doi:10.
1016 /S2352-3018(21)00006-0[7] Ryan CP.
"Epigenetic clocks": Theory and applications in human biology [published online ahead of print, 2020 Aug 26].
Am J Hum Biol.
2020;e23488.
doi: 10.
1002/ajhb.
23488[8] Levine AJ, Quach A, Moore DJ, et al.
Accelerated epigenetic aging in brain is associated with pre-mortem HIV-associated neurocognitive disorders.
J Neurovirol.
2016;22(3):366-375 .
doi:10.
1007/s13365-015-0406-3[9] Sánchez-Conde M, Rodriguez-Centeno J,Dronda F, et al.
Frailty phenotype: a clinical marker of age acceleration in the older HIV-infected population.
Epigenomics.
2019;11(5):501-509.
doi:10.
2217/epi-2018-0130 Edit | Ying Yuyan
