Common pathologies of aging.

<p>Incidence of disparate pathological conditions all showing a strong correlation with advanced human age. Many of these same conditions are also seen in aged dogs.</p

Some conserved pathways and interventions of aging.

<p>**There is indirect evidence that each of these is associated with health span or longevity in humans. For specific examples, see references [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002131#pbio.1002131.ref008" target="_blank">8</a>–<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002131#pbio.1002131.ref049" target="_blank">49</a>] and <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002131#pbio.1002131.s001" target="_blank">S1 Text</a>. Abbreviations: AMPK, 5ʹ adenosine monophosphate-activated protein kinase; ILS, insulin-like signaling; mTOR, mechanistic target of rapamycin; NAD, nicotinamide adenine dinucleotide; SOD, superoxide dismutase.</p><p>Some conserved pathways and interventions of aging.</p

Why Is Aging Conserved and What Can We Do about It?

<div><p>The field of aging research has progressed rapidly over the past few decades. Genetic modulators of aging rate that are conserved over a broad evolutionary distance have now been identified. Several physiological and environmental interventions have also been shown to influence the rate of aging in organisms ranging from yeast to mammals. Here we briefly review these conserved pathways and interventions and highlight some key unsolved challenges that remain. Although the molecular mechanisms by which these modifiers of aging act are only partially understood, interventions to slow aging are nearing clinical application, and it is likely that we will begin to reap the benefits of aging research prior to solving all of the mysteries that the biology of aging has to offer.</p></div

Environmental signals that modulate growth and reproduction also modulate aging.

<p>Organisms have evolved to grow and reproduce rapidly when environmental conditions, including temperature, oxygen levels, and food availability, are within optimal ranges. When these parameters are suboptimal but not lethal, organisms tend to become stress resistant and, perhaps as a by-product, longer lived. Conserved sensory pathways mediate this relationship, although there is also evidence that signals from the germ line can affect stress resistance and longevity and vice versa.</p

TOR Kinase Mediates Important Cellular Responses Implicated in Extended Longevity

<div><p>During periods of nutrient availability, TOR kinase is activated, leading to G1 progression, translation initiation, increased ribosome biogenesis, and a suppression of autophagy and the stress response.</p><p>When TOR is inactivated, either by DR or by the TOR inhibitor rapamycin, a cellular response is initiated that turns down protein translation and cell growth, and increases protein turnover and genes involved in the stress response. The conserved cellular regime that is the result of inactivated TOR kinase increases both replicative and chronological life span in yeast.</p></div

Strains used in this study.

<p>Strains used in this study.</p

Correlation between culture pH and chronological life span.

<p>BY4743 and RM11 cells were aged in synthetic complete medium with different carbon sources as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024530#pone-0024530-t003" target="_blank"><b>Table 3</b></a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024530#pone-0024530-g005" target="_blank"><b>Figure 5</b></a>. Culture pH was measured at either day 2 or day 4 of the experiment.</p

Adjusting synthetic complete medium to a pH of 6.0 extends chronological life span.

<p>Life span extension from buffering at pH 6.0 using a citrate phosphate buffer was statistically significant (p<0.05) in (<b>A</b>) diploid, (<b>B</b>) haploid mating type <i>α</i>, and (<b>C</b>) haploid mating type <b>a</b> of BY4743 (BY) and RM11 (RM). Error bars indicate standard deviation across biological replicates. Corresponding survival integral and p-values are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024530#pone-0024530-t002" target="_blank">Table 2</a>.</p

Effect of carbon source on chronological life span correlates with pH of the culture medium after 48 hours of culture.

<p>The effect of different carbon sources on chronological life span is shown for diploid (<b>A</b>) BY4743 or (<b>B</b>) RM11 cells. Cells were aged in synthetic complete medium with the indicated carbon source. Control concentrations for all carbon sources were tested at 2% w/v except ethanol and glycerol which were tested at 3%. Dietary restricted (DR) concentrations were at 0.5% for all sources except ethanol and glycerol which were reduced to 1%. Survival integral (SI) values represent the area under the survival curve between day 2 and day 26 and error bars represent the standard deviation across biological replicates. The survival integral values for growth in different carbon sources correlates significantly with culture pH after 48 hours in diploid (<b>C</b>) BY4743 or (<b>D</b>) RM11 cells. A similar correlation was observed for pH after 4 days of culture (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024530#pone-0024530-t004" target="_blank">Table 4</a>).</p

Two Pathways Determine Yeast Longevity

<p>The longevity of mother cells can be modified by at least two independent interventions: altered ERC levels and CR. In cells lacking Sir2 but containing Fob1, senescence due to ERCs predominates, causing an extremely short life span that cannot be increased by CR. In cells lacking <i>FOB1</i>, ERCs are greatly reduced and the CR pathway predominates. The presence or absence of Sir2 does not impact the longevity benefits of CR under this condition.</p