Chinese Academy of Sciences scholar Cell issued an article: The revival of human genome archaeviruses drives aging

The co-evolutionary relationship between viruses and humans has a long history, and the confrontation between the two has never stopped over time
.
In this protracted war, on the one hand, viruses make human beings suffer from diseases and even death, and in the process continue to use and modify the human genome; On the other hand, the human immune system will actively fight the invasion of viruses, so that the viral sequences integrated into the human genome are gradually taken over by the genetic regulatory system of the host cell and co-evolve
.
Endogenous retroviruses (ERVs) are the remains of ancient retroviral invasions that integrated into the human genome millions of years ago - "ancient virus fossils"
.
In the long years, a large amount of ERV genetic information has been captured by human cells, and through mutations, deletions and other mutations to become the "dark matter" in the human genome lurking, accounting for about 8% of the human genome sequence, becoming an important genetic memory
.
Human beings and ERV can be described as "one foot tall and one foot high", and in the conception and evolution of life, it seems to present a harmonious symbiotic scene
.

Aging is one of the
biggest risk factors for chronic diseases in humans.
Cellular senescence is an important cause of senescence and the development of various aging-related diseases, and epigenetic programmed changes are considered to be the key factors determining the process of
cellular senescence.
The human genome has many "aging" signals, and these aging information streams are usually tightly regulated by epigenetics and are silent, but in the process of aging, due to epigenetic disorders, these "aging" signals escape control and activate a series of aging processes
in cells.
However, it is unknown
whether ERV archaea elements, which occupy a large proportion of the human genome sequence and are as silent as "extinct volcanoes", participate in the programmed regulation of aging.
Can ERV elements sleeping in the human genome escape host surveillance and be reawakened during aging? How does the awakening and eruption of these "extinct volcanoes" affect the aging of cells and tissues? Can the revival of ERV archaea be used as a marker for measuring human biological age and a molecular target for intervention in aging? These key scientific questions need to be elucidated
.

On January 6, Liu Guanghui's research group and Qu Jing's research group of the Institute of Zoology, Chinese Academy of Sciences, in collaboration with Zhang Weiqi's research group of the Beijing Institute of Genomics of the Chinese Academy of Sciences, published a research paper
entitled Resurrection of endogenous retroviruses during aging reinforces senescence online in Cell 。 This study found for the first time that the young ERV subfamily is reawakened in the process of cellular aging, put forward the theory that archaeal virus revival mediates aging programmatic and contagious, and innovatively developed a multidimensional intervention strategy
to block the revival and spread of ERV archaea virus to delay aging.

The researchers used different aging research systems established by the team (including childhood Progeria syndrome, adult Progeria syndrome, replicative aging, human mesenchymal stem cell models of physiological aging, human fibroblast aging models, and physiological and pathological multi-organ aging models of mice, monkeys and humans), combined with high-throughput strand-specific transcript sequencing, genome-wide DNA methylation sequencing, high-resolution single-molecule RNA/DNA in situ hybridization, Multidisciplinary techniques such as immunoelectron microscopy and highly sensitive droplet digital PCR have found that epigenetic desuppression (such as heterochromatin reduction) in senescent cells leads to transcriptional activation of ERV in the genome and translation of viral proteins, which are packaged into viral particles
。 On the one hand, the reverse transcription products of ERV in senescent cells induce cellular senescence and inflammation by activating the cGAS-STING natural immune pathway; On the other hand, ERV virus particles released by senescent cells can effectively transmit and amplify aging signals between organs, tissues and cells through paracrine or humoral mediation, and eventually cause young cells to age
due to "infection".
In-depth mechanistic studies have shown that the appearance of ERV reverse transcripts in the cytoplasm of host cells activates the viral defense mechanisms
inherent in naïve cells and infected cells.
This instinctive cellular antiviral response is intended to reduce the damage of the virus, but contrary to expectations, these defensive mechanisms promote premature cell aging
.
This study elucidates the whole chain mechanism
of ERV archaeal virus in the genome of senescent cells, which triggers cell aging, transmits aging signals with the help of viral particles, and infects young cells 。 Furthermore, through the analysis of different life cycle links such as ERV archaeonvirus latent, resurrection, and cell-to-cell transmission, an intervention strategy to effectively inhibit the revival and removal of viral particles by ERV archaea was developed, that is, through the development of CRISPR gene silencing system based on ERV regulatory elements, small molecule inhibitory drugs targeting reverse transcriptase, neutralizing antibodies targeting viral envelope proteins, etc.
, to block multiple links such as ERV transcription, reverse transcription, and viral cascade infection.
In turn, the aging of tissues and the body is delayed
.

The study systematically defined and revealed aging-i nduced r esurrection of endogenousretrov irus, AIR-ERV) can be used as the driving force and measurement marker of aging of cells, organs and even the body, providing a new theoretical basis for the programmatic, cascade amplification and interventionability of aging, and providing important clues and ideas
for the scientific evaluation and early warning of human aging, aging and the prevention and treatment of aging-related diseases 。 In terms of theory, the research creatively proposed the programmatic, cross-cellular transmission and interventionability of aging, and confirmed the revival of ERV archaea as a new aging clock and driving factor.
In terms of technology, the research comprehensively uses cutting-edge cross-cutting technologies such as multidimensional epigenome, transcriptional targeted manipulation, single-molecule imaging, virology, immunology, chemical biology and molecular pathology to dynamically capture multiple biological processes such as revival, packaging, granulation, cross-cell transmission and activation of natural immune pathways of ERV archaea viruses, characterize the life cycle trajectory of ERV in aging organisms, and create a new aging research paradigm.
In terms of translational medicine, research has developed diversified aging intervention technologies targeting different links of ERV archaeonvirus revival chain, which provides new strategies for the prevention and treatment of aging-related diseases, and has potential application value
in the field of aging translational medicine.

In summary, this study suggests that the virus code has been integrated into human aging and life regulation procedures in ancient times, and decoding ancient viral elements in the genome will help to analyze the mechanism of human aging, the law of health and longevity, and the causes
of various geriatric diseases.
The resurrection of ERV archaea may provide a new way
to explore the "Pandora's box" of aging.
The opening of the "magic box" has opened up a new scientific territory for exploring the law of aging, and brought new hope
for the prevention and treatment of geriatric diseases.
In the future, more scientific questions will arise around the activation of ERV archaeviruses accompanying aging, such as, can ERV reverse transcripts be reintegrated into the host genome to mediate aging-related genomic instability? Do ERV archaeal virus sequences have genetic polymorphisms in the human genome? Is it closely related to health in old age? Is ERV resuscitation and infection efficiency tissue and cell type specific? Does ERV activation selectively drive the onset of specific aging-related diseases? Can ERV testing in body fluids be used for the assessment and early warning of aging and geriatric diseases? Which targeting strategies for the ERV life cycle are most effective for clinical aging and disease interventions? It is hoped that in the future, with the deepening of scientific research and the increasing innovation of technological means, these mysteries
can be solved one by one.

The research work is supported
by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the Beijing Municipality.
The Institute of Genetics and Development of the Chinese Academy of Sciences, the Beijing Institute of Stem Cell and Regenerative Medicine, Xuanwu Hospital of Capital Medical University, Kunming University of Science and Technology, Huazhong Agricultural University, Peking University and Beijing Hospital participated in the research
.

Paper link

Figure 1.
HERVK viral RNA (left) and viral particles (RVLP, right) aggregate in senescent human cells

Figure 2.
Mechanism and intervention strategies of endogenous archaea revival driving aging

Figure 3: Endogenous archaea resurrection drives the opening of the "Pandora's box" of aging