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Gustavo Barja de Quiroga

nucleus) broadly depicts known mechanisms of control of longevity at cell level. Different kinds of dietary restrictions (DR, PR, MetR) and
rapamycin (signals coming from the environment) alter humoral, endocrine, and finally cytosolic pre-PAP signaling proteins like mTOR,
AMPK, and many others (part A, left of figure). In many cases this modifies the expression (through transcription factors like FOXOs, TEFB

and others) of nuclear genes likely organized as Gene Clusters of Aging (153) of the PAP (part B center). PAP output (solid arrows leaving the
nucleus on the right of the figure), in turn, modifies the activity of at least three Aging Effectors (shown in italics, Part C, right): a) Mitochondria
(including mitROSp), b) fatty acid double bond index (DBI), and c) and likely Autophagy. The integrated responses of the aging effectors to the
DRs and rapamycin, or to knocking out GH or IGF-1/insulin-like signaling genes increases longevity. Across species the same (plus additional)
genes forming the PAP are constitutively active at different levels in species with different longevities. In some cases the signals can reach the
mitochondria directly by-passing the nuclear PAP, as it is the case for MetR possibly lowering cysteine thiol groups at complex I (Ref. 159).
The action of other possible effectors of aging like telomere shortening or apoptosis is likely limited to mitotic tissue cells and evidences for
their validity are still lacking. mtDNA deletions, and mtDNA fragments inserted in the nucleus increase with age (139,147-49) and can

contribute to aging (139,149). Mitochondrial ROSp (and updated MFRTA) are not alternative to the humoral (e.g. insulin-IGF-1 like) or
cytosolic proteins (e.g. mTOR or S6K) part of CARS and signaling to PAP. Instead, the three main kinds of cellular processes (A, B and C)
work together integrated into a single CARS to control longevity in each species and to finely adjust changes in longevity inresponse to DRs or
pro-longevity drugs like rapamycin. During 40 % DR lowered mitROSp and increased autophagy execute the PAP response. At 80 % (but not
40 %) MetR, decreasing the DBI is also a recruited response. These three aging effectors can be involved in the change in longevity between
species. Epigenetics can be also involved in changing the PAP gene expression level. DBI (double bond index) indicates the number of
double bonds of membrane fatty acids (DBI). ECF = extracellular fluids; MFRTA= mitochondrial free radical theory of aging.

Intensive aging research during the present century, the expression of PAP genes involved in the control of
including studies with gene knockout and transgenic longevity. These have been proposed to be organized in
animals, has clarified a series of important facts different but interrelated Gene Clusters of Aging,
concerning the CARS: analogously to the Hox genes located in four clusters and
involved in the control of development from embryo to
a) Inactivation of many single genes leads to an adult (153).
increase in mouse longevity (up to, ca., 40 %). Most
importantly, those genes are highly conserved in evolution e) Most long-lived mouse mutants live up to 40 %
which agrees with the concept that aging is an adaptation longer than the wild type animals. This, most interestingly,
that increases biological fitness at group or higher level. coincides with the amount of longevity extension elicited
Thus, aging constitutes a good example of an adaptation by DR (also up to 40 %). Many of those known genes
covered under the umbrella of the modern concept of mainly codify for proteins involved in GH/ or insulin/IGF-
Multilevel Selection. Many of those genes are the 1-like Pre-nuclear Signaling, or cytoplasmic pre-PAP
homologous in organisms so different as yeast, nematodes cytosolic signaling proteins, or nuclear transcription
like C. elegans, insects like Droshophila, and many factors like FOXOs or TFEB.
vertebrates including mammals and humans. Therefore,
aging is a very old adaptation of most multicellular and f) The cytosolic signaling proteins work in many cases
even at least the unicellular eukaryotic life. by modification of nuclear PAP activity. The induced
changes in gene expression modify the levels of specific
b) Although DR (and MetR) can control aging in part proteins corresponding to PAP output. The final result is
by directly modifying the aging effectors, they also bring the variation in activity level of the systems finally
about changes in expression of a large number of nuclear controlling the rate of aging, the cellular Post-nuclear
genes (78,150,151). The modified expression of those Aging Effectors. Three of them have been already
genes, in turn, modifies the activity of the three known identified:
aging effectors too.
(i) The Mitochondria, and their rate of mitROSp at
c) The different kinds of DRs increase mouse longevity complex I
by modifying the expression levels of hundreds of genes,
as shown by many microarray-based studies. Those (ii) The degree of Unsaturation of Cell Membrane
changes are species- and tissue-specific. This, together Fatty Acids (DBI); and
with the increase in longevity after inactivation of single
genes codifying for pre-nuclear hormones, their receptors, (iii) Likely, the Macro-Autophagocytosis (Autophagy)
cytoplasmic signaling proteins or transcription factors (part system.
A of the CARS), constitutes robust evidence that a Pro-
Aging Program (PAP) exists in the cell nucleus. These three main effectors are operative in aerobic
vital tissues, both mitotic and post-mitotic. The action of
d) DR and MetR signal the abundance of food or other possible effectors like telomere shortening or
proteins available for feeding in the external world to the apoptosis would be restricted to mitotic cells, of smaller
cell inside the body using humoral factors like insulin, relevance for aging. Therefore increased longevity, both
GH/IGF-1, or blood amino acids like methionine. These in during DRs and between different animal species, is
turn modify the activity of many cytoplasmic signaling obtained through decreased mitROSp at complex I, and
proteins like mTOR, S6K, AMPK, AKT, PI3K, FGF21, increased autophagy. A decrease in cell membrane DBI is
ULK1, NFkB, HIF and many others. Many of those involved also in increasing longevity across species.
signals enter the nucleus, where, through the action of
transcription factors like FOXOs or TFEB (152), modify The first two aging effectors (mitROSp and DBI) were
identified in the 1990´s. With these two the key to long life
is to decrease the rate of generation of (oxidative) damage
at mitochondria; and to have cellular membranes,

68 @Real Academia Nacional de Farmacia. Spain