variance is constrained as expressionvalues approach zero (Supplemental File), explaining the decrease in variance with age.

We found that as the organism ages,most TF-TG pairs displayed a decrease in range (Figure 2D) but that the variance also decreased

coarse-15grained

CC is expected to decrease with variability

CC isexpected to increase with range.

noise can alternatively be defined as theinformation lost between input and output. We term this as ‘noise in input’ at the regulator end,20and ‘noise in output’ at the effector end

In some cases, greater variance facilitates better regulation

A higher Shannon entropy indicates that the probabilitydistribution of gene expression becomes more uniform, thereby decreasing the ability to reliablypredict gene expression.

Collectively, these data suggest that aging may be accompanied by areallocation of resources that favor messages crucial to maintenance of stability and survival.

Free radicals,ionizingradiation,

Although the model is concise(an organism is considered as a simple set of cells)

pleiotropic

BSA

10xChromium to capture single cell transcriptomes.

samplemultiplexing (

PBS

perfused

FACS

We then generated 79,488 single cell transcriptomes from the SVZ neurogenic regionfrom young (5 month) and old (23 month),

However, shared genes carry a disproportionate weight within theclocks, with coefficients approximately 40% larger in magnitude

(R = 0.41-0.89, error = 2.3 - 4.6 months)

Even though all clocks were trained on aNSC-NPC‘proliferative fraction’, the microglia and oligodendrocytes biological age clocks performedbetter than aNSC-NPC ones.

MTR

One hypothesis is that general prolif-eration can combine with positional informationto up-regulate any regionally specified progenitorclass neara wound, regardless of whether its targettissue is missing

issue-specific resection of planarianeyes does not cause up-regulation of eye progen-itors. In this case, eye regeneration is explainedby a constitutive basal rate of eye progenitor pro-duction and the fact that newly regenerating eyesare constituted by young cells and have fewertotal cells that could die per unit time

he tgs-1 tran-script itself perdures in a subset of G1-annotatedneoblasts with neural markers;

neoblast) being FSTF transcript-low and thesmedwi-1-low daughter (a postmitotic differen-tiating cell) being FSTF-transcript high

In this model, a specialized neoblast can divideto produce cells with asymmetric outcomes,with one daughter being a neoblast capable ofchoosing a new fate in its next round of celldivision

smedwi-1

Single-step fatemodel. Neoblasts can choose a fate and produce a differentiated cell in the course of a single cell division.

sin-gle-cell qPCR

mesenchymal

Because a smallplanarian fragment must accomplish regenera-tion with existing mass, blastemas cannotregrow all missing tissues at their original scale

to initiate exit from pluripotency and to restrict cells to spe-cific differentiation paths.

opens thequestion as to how regeneration signals instruct PSCs to pro-duce the appropriate number and type of progenitor neoblastsin response to different regeneration requirements.

soxP-3

Therefore, high levels of PIWI-1 protein appear pri-marily associated with actively dividing cells,

a heterogeneous number of piwi-1 transcripts

clonal expansion

Only 7 out of120 injected neoblasts resulted in successful restoration of hostviability, suggesting extensive functional heterogeneity in theneoblast population

ingle-cell transplantations demon-strated that a single neoblast is capable of rescuing lethally irra-diated hosts by reconstituting all cell types in the animal’s body

indicating a highly significant association between induction of cellular stress resistance and C. elegans longevity

However, 16/54 negative control compounds tested (i.e., those that did not induce MTF stress resistance) were also able to significantly increase fly lifespan (29.6% of the total compounds tested; p=0.07 for hits versus negative controls)

Among the 70 unique compounds that significantly increased MTF stress resistance that were tested in flies, 12 significantly increased fly lifespan in either or both sexes (17.1% of the total compounds tested)

optimizing growth media, seeding density, and incubation time.

560 (

0.0200

0.02

1005

low dose of doxycycline

metabolites

hematopoietic cells

As expected, all of these were increased with aging; however, their levels 273 did not decline in any of the two cohorts of very old-OSKM mice

Interestingly, the large majority of genes 188 upregulated by OSKM in old mice (pink dots) corresponded to genes with 189 reduced expression upon aging

We conclude that a single period 172 of OSKM expression is able to rejuvenate a fraction of the methylation changes 173 that occur with aging in promoters and enhancers.

(“very old”, n=6), 147 and reprogrammable mice

MspI-based Reduced Representation Bisulfite 96 Sequencing

the histological changes 81 observed in the pancreas after one week of OSKM induction were reversed two 82 weeks after removal of doxycycline

dysplasia in which the tissue alters its normal architecture 66 and cells lose differentiation markers

(Or shelter hah) the end of the telomere from the DNA repair machinery: DNA looks like a continuous strand for most of its length except at the ends, so it is efficient for the cell to recognise 'ends' of this strand as breaks, and try to repair them. But of course you wouldn't want that in the end of the chromosome, because it's a legitimate feature. However, if true damage happens to the telomeric section, it's not going to be repaired, so telomeres steadily accumulate damage.

there is support for continued trials of metformin in humans, and there is some evidence that it could improve diseases associated with aging; however we still don't know if it would help with increasing maximum lifespan in humans.

C. Elegant