Analyzing the Acceleration of Aging in Old Mice

Researchers looked at the transcriptome of aged mice to assesswhich genes are being expressed, and to what degree. The differences between mice in early and late old age are large. This reflects what we see in humans. There is a great deal of difference between a 60-year-old and an 80-year-olds. The observed differences start at the cell function, which emerge in response to rising levels of cell and tissue damage.

* Only 30% of adults aged 45 – 64 years have at least two chronic conditions
* 65% of those aged 65 – 84 years
* approximately 80% of those aged 85 years and older have the same conditions.

In mice, those ranging from 18 to 24 months-of-age are comparable to humans of 56 – 69 years-of-age. They hve “young-old” age characteristics. Mice aged 26 months and older can be considered as “old-old”. Mice 22 – 24 months of age is when morphological changes consistent with human sarcopenia (muscle wasting) start in mice and rats. This period is when skeletal muscle mass and grip strength decline progressively with age, exhibiting prominent changes at 24-28 months of age, while whole-body mass and lean mass were relatively stable or only marginally declined. Another significant distinction between the young-old and old-old groups is survivorship; 24- and 28-month-old mice exhibit 85% and 50% survival rates, respectively. Based on this rapid decline in muscle mass and survivorship with age, researchers assumed that aging accelerates in “late life” in a manner different from that in the slow aging mode before then.

Therefore, to investigate these age-associated diseases, it may be beneficial to divide the elderly into groups and inspect the resultant subgroups separately for pathophysiological differences, and other deteriorations or weaknesses.

Researchers observed a comprehensive change in the transcriptome of skeletal muscle during L-aging. The transcriptomes of old-old samples were markedly altered, exhibiting a drastic change in the forward path manifested by the transcriptomes of the younger age groups. Many genes were significantly changed, and of them, the EL-aging genes demonstrated fluctuation in their expression levels with a successive change during the E-aging and L-aging period. However, these changes among old-old samples did not seem to be random but rather synchronic in a variety of gene sets. For example, increasingly expressed EL-aging genes in the L-aging group were significantly enriched in the immunity- and inflammation-related gene sets, whereas decreasingly expressed genes were depleted in the mitochondrial function and translation terms.

We assume that during the E-aging, the EL-aging genes are either in highly expressed or tightly repressed states and multi-layered regulatory systems struggle for transcriptional homeostasis at the expense of cellular energy. During the L-aging, as cellular energy and resources become limited, cells and their transcriptional regulatory systems give way to being decompensated throughout the genome, as evidenced by the upturn and downturn shifts of expression. As such dysregulations over the genome continue unchecked and wide-spread, it eventually results in systemic aging. Likewise, the tension-releasing shift can passively occur in aged, decompensated cells, or there may exist an unknown factor that triggers such changes yet to be identified. At the molecular level, within a cell, genetic and epigenetic regulatory devices that act on the gene sets (Figure 4C) involving EL-aging genes have hitherto managed to homeostatically control the transcriptional milieu over the genes. These devices may break down by increasing stress and tension elicited with aging, leading to the awry expression of genes. Some early EL-aging genes, when altered in expression levels, may accelerate cells to transit to the late phase of aging and further transcriptionally alter the other downstream EL-aging genes. If we could identify these leading EL-aging genes and determine how to keep them safe and unharmed from causes and results of aging, we could delay the oncoming L-aging and prolong the slow E-aging. This can undoubtedly be the genuine way for healthy aging.

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