Short-lived Strains Research Articles

Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span

Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss, and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with naturally short-lived animals exhibit a loss of dopamine neurons without generalized neurodegeneration, while animals from long-lived strains retain dopamine neurons across age. Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress, and vulnerability to silencing the familial PD gene parkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (Gcl) overexpression is sufficient to normalize ROS levels, extend life span, and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity. These findings may be relevant to human PD pathogenesis, where glutathione depletion is reported to occur in the idiopathic PD patient brain through unknown mechanisms. Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in the human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.

Characterizing a panel of amino acid auxotrophs under auxotrophic starvation conditions.

Auxotrophic strains starving for their cognate nutrient, termed auxotrophic starvation, are characterized by a shorter lifespan, higher glucose wasting phenotype, and inability to accomplish cell cycle arrest when compared to a "natural starvation," where a cell is starving for natural environmental growth-limiting nutrients such as phosphate. Since evidence of this physiological response is limited to only a subset of auxotrophs, we evaluated a panel of auxotrophic mutants to determine whether these responses are characteristic of a broader range of amino acid auxotrophs. Based on the starvation survival kinetics, the panel of strains was grouped into three categories-short-lived strains, strains with survival similar to a prototrophic wild type strain, and long-lived strains. Among the short-lived strains, we observed that the tyrosine, asparagine, threonine, and aspartic acid auxotrophs rapidly decline in viability, with all strains unable to arrest cell cycle progression. The three basic amino acid auxotrophs had a survival similar to a prototrophic strain starving in minimal media. The leucine, tryptophan, methionine, and cysteine auxotrophs displayed the longest lifespan. We also demonstrate how the phenomenon of glucose wasting is limited to only a subset of the tested auxotrophs, namely the asparagine, leucine, and lysine auxotrophs. Furthermore, we observed pleiotropic phenotypes associated with a subgroup of auxotrophs, highlighting the importance of considering unintended phenotypic effects when using auxotrophic strains especially in chronological aging experiments.

A Method for Evaluating Brain Deformation Under Sagittal Blunt Impacts Using a Half-Skull Human-Scale Surrogate.

Physical head models consisting of a half, sagittal plane skull, brain, and neck were constructed and subjected to crown and frontal impacts at two impact speeds. All tests were recorded with a high-speed camera at 1000 frames per second. Motion of visual markers within brain surrogates were used to track deformations and calculate spatial strain histories in 6 brain regions of interest. Principal strains, strain rates and strain impulses were calculated and reported. Higher impact velocities corresponded to higher strain values across all impact scenarios. Crown impacts were characterized by high, long duration strains distributed across the parietal, frontal and hippocampal regions whereas frontal impacts were characterized by sharply rising and falling strains primarily found in the parietal, frontal, hippocampal and occipital regions. High strain rates were associated with short durations and impulses indicating fast but short-lived strains. 2.23 m/s (5 mph) crown impacts resulted in 53% of the brain with shear strains higher than 0.15 verses 32% for frontal impacts. The results reveal large differences in the spatial and temporal strain responses between crown and forehead impacts. Overall, the results suggest that for the same speed, crown impact leads to higher magnitude strain patterns than a frontal impact. The data provided by this model provides unique insight into the spatial and temporal deformation patterns that have not been provided by alternate surrogate models. The model can be used to investigate how anatomical, material and loading features and parameters can affect deformation patterns in specific regions of interest in the brain.

Multistage work hardening assisted by multi-type twinning in ultrafine-grained heterostructural eutectic high-entropy alloys

High strength of materials usually comes with low ductility due to the lost or short-lived strain hardening. Here, we uncover a sequentially-activated multistage strain hardening (SMSH) that allows for sustained and effective strain-hardening capability in strong ultrafine-grained eutectic high-entropy alloy (EHEA). Consequently, exceptional ductility is realized in an ultrafine-grained EHEA, accompanied with high ultimate strength. We demonstrate that the SMSH is derived from a coordinated three-level design on structural heterogeneity, grain-size control, and intragranular composition modification, which enables the sequential activation of stress-dependent multiple hardening mechanisms. Furthermore, despite the well-known low twinning propensity due to ultrafine grains and medium-to-high stacking fault energies of prototype EHEAs, our coordinated design sequentially activates three types of deformation twinning to assist this SMSH. This work sheds light on the SMSH effect assisted by multi-type twinning previously unexpected in ultrafine-grained EHEAs, and thereby represents a promising route for improving ductility of high-strength materials.

Spontaneous mutations in CYC8 and MIG1 suppress the short chronological lifespan of budding yeast lacking SNF1/AMPK.

Chronologically aging yeast cells are prone to adaptive regrowth, whereby mutants with a survival advantage spontaneously appear and re-enter the cell cycle in stationary phase cultures. Adaptive regrowth is especially noticeable with short-lived strains, including those defective for SNF1, the homolog of mammalian AMP-activated protein kinase (AMPK). SNF1 becomes active in response to multiple environmental stresses that occur in chronologically aging cells, including glucose depletion and oxidative stress. SNF1 is also required for the extension of chronological lifespan (CLS) by caloric restriction (CR) as defined as limiting glucose at the time of culture inoculation. To identify specific downstream SNF1 targets responsible for CLS extension during CR, we screened for adaptive regrowth mutants that restore chronological longevity to a short-lived snf1∆ parental strain. Whole genome sequencing of the adapted mutants revealed missense mutations in TPR motifs 9 and 10 of the transcriptional co-repressor Cyc8 that specifically mediate repression through the transcriptional repressor Mig1. Another mutation occurred in MIG1 itself, thus implicating the activation of Mig1-repressed genes as a key function of SNF1 in maintaining CLS. Consistent with this conclusion, the cyc8 TPR mutations partially restored growth on alternative carbon sources and significantly extended CLS compared to the snf1∆ parent. Furthermore, cyc8 TPR mutations reactivated multiple Mig1-repressed genes, including the transcription factor gene CAT8, which is responsible for activating genes of the glyoxylate and gluconeogenesis pathways. Deleting CAT8 completely blocked CLS extension by the cyc8 TPR mutations on CLS, identifying these pathways as key Snf1-regulated CLS determinants.

Transcriptome States Reflect Imaging of Aging States.

In this study, we describe a morphological biomarker that detects multiple discrete subpopulations (or "age-states") at several chronological ages in a population of nematodes (Caenorhabditis elegans). We determined the frequencies of three healthy adult states and the timing of the transitions between them across the lifespan. We used short-lived and long-lived strains to confirm the general applicability of the state classifier and to monitor state progression. This exploration revealed healthy and unhealthy states, the former being favored in long-lived strains and the latter showing delayed onset. Short-lived strains rapidly transitioned through the putative healthy state. We previously found that age-matched animals in different age-states have distinct transcriptome profiles. We isolated animals at the beginning and end of each identified state and performed microarray analysis (principal component analysis, relative sample to sample distance measurements, and gene set enrichment analysis). In some comparisons, chronologically identical individuals were farther apart than morphologically identical individuals isolated on different days. The age-state biomarker allowed assessment of aging in a novel manner, complementary to chronological age progression. We found hsp70 and some small heat shock protein genes are expressed later in adulthood, consistent with the proteostasis collapse model.

An alternative model for studying age-associated metabolic complications: Senescence-accelerated mouse prone 8

Rodent animal models take at least 18months to develop aging phenotypes for researchers to investigate the mechanism of age-related metabolic complications. Senescence-accelerated mouse prone 8 (SAMP8) shortens the process of aging and may facilitate an alternative model for studying age-related insulin resistance. The short-lived strain SAMP8 and two long-lived strains SAM resistant 1 (SAMR1) mice and C57BL/6 mice at 12 (young) and 40weeks old (old) were used in the present study. Glucose tolerance test, histology and signaling pathways involved in lipid metabolism in adipose tissue and liver and key components of insulin signaling pathway in the skeletal muscle were determined in these three strains. We found that short-lived SAMP8 mice developed symptoms of insulin resistance including hyperglycemia, hyperinsulinemia, and impaired glucose tolerance in association with adipocyte hypertrophy and ectopic lipid accumulation in liver and muscle at 40-wk.-old. Significantly increased serum IL-6, leptin, and resistin levels and adipogenic transcription factor PPARγ and macrophage marker F4/80 mRNA expression in adipose tissues were observed in old SAMP8 mice, compared with that in young SAMP8 mice. Marked increases in SREBP1 and PPARγ and a decrease in PPARα at mRNA level in accordance with activation of mTOR/Akt pathway were contributed to hepatic lipid accumulation in old SAMP8 mice. Down-regulation of insulin signaling pathway including IRβ, IRS1, and AS160 at protein level in skeletal muscle was observed in old SAMP8 mice. At 40-wk.-old, both long-lived SAMR1 and C57BL/6 mice have not been fully developed age-related metabolic disorders including insulin resistance and visceral fat expansion in line with fewer defects in lipid metabolism and skeletal muscle insulin signaling pathway. In conclusion, our data suggest the suitability of the SAMP8 mice as a model for studying age-related metabolic complications.

P 193 - Redox control of the 20 S proteasome gating: Implications on the chronological life span of yeast cells

Two Cys residues located in the α5-subunit of the yeast 20 S proteasome (20SPT) are post-translationally modified by S-glutathionylation. Such modification implies on the opening of the 20SPT gate when compared to the DTT-reduced purified preparations. The site-specific mutation of the highly conserved (yeast to human) α5-Cys76 residue induced either decreased cell viability or life span when compared to the wild type strain. The α5-C76S-mutated strain presented decreased resistance to oxidative stress without any alteration on major redox parameters. The closed gate conformation of the 20SPT pool in that short-lived strain represents 70% of total 20SPT pool against 35% in the wild type counterpart. Mass spectrometry analysis of the α5-subunit in the α5-C76S-mutated strain showed S-glutathionylation of the remaining α5-C221 residue suggesting that redox modification of the conserved α5-C76, but not of the α5-C221, is the one involved in the gate opening. Circular dichroism analyses of recombinant α5-WT and α5-C76S subunits showed similar pattern between them regarding their secondary and tertiary structures. The differences between the wild type and short-lived strains regarding prevalence of 20SPT gate conformation, clearly demonstrate that the 20SPT opening is relevant to maintain cellular homeostasis and life span.

Mitochondrial Efficiency-Dependent Viability of Saccharomyces cerevisiae Mutants Carrying Individual Electron Transport Chain Component Deletions.

Mitochondria play a crucial role in eukaryotic cells; the mitochondrial electron transport chain (ETC) generates adenosine triphosphate (ATP), which serves as an energy source for numerous critical cellular activities. However, the ETC also generates deleterious reactive oxygen species (ROS) as a natural byproduct of oxidative phosphorylation. ROS are considered the major cause of aging because they damage proteins, lipids, and DNA by oxidation. We analyzed the chronological life span, growth phenotype, mitochondrial membrane potential (MMP), and intracellular ATP and mitochondrial superoxide levels of 33 single ETC component-deleted strains during the chronological aging process. Among the ETC mutant strains, 14 (sdh1Δ, sdh2Δ, sdh4Δ, cor1Δ, cyt1Δ, qcr7Δ, qcr8Δ, rip1Δ, cox6Δ, cox7Δ, cox9Δ, atp4Δ, atp7Δ, and atp17Δ) showed a significantly shorter life span. The deleted genes encode important elements of the ETC components succinate dehydrogenase (complex II) and cytochrome c oxidase (complex IV), and some of the deletions lead to structural instability of the membrane-F1F0-ATP synthase due to mutations in the stator stalk (complex V). These short-lived strains generated higher superoxide levels and produced lower ATP levels without alteration of MMP. In summary, ETC mutations decreased the life span of yeast due to impaired mitochondrial efficiency.

Rec-8 dimorphism affects longevity, stress resistance and X-chromosome nondisjunction in C. elegans, and replicative lifespan in S. cerevisiae.

A quantitative trait locus (QTL) in the nematode C. elegans, “lsq4,” was recently implicated by mapping longevity genes. QTLs for lifespan and three stress-resistance traits coincided within a span of <300 kbp, later narrowed to <200 kbp. A single gene in this interval is now shown to modulate all lsq4-associated traits. Full-genome analysis of transcript levels indicates that lsq4 contains a dimorphic gene governing the expression of many sperm-specific genes, suggesting an effect on spermatogenesis. Quantitative analysis of allele-specific transcripts encoded within the lsq4 interval revealed significant, 2- to 15-fold expression differences for 10 of 33 genes. Fourteen “dual-candidate” genes, implicated by both position and expression, were tested for RNA-interference effects on QTL-linked traits. In a strain carrying the shorter-lived allele, knockdown of rec-8 (encoding a meiotic cohesin) reduced its transcripts 4-fold, to a level similar to the longer-lived strain, while extending lifespan 25–26%, whether begun before fertilization or at maturity. The short-lived lsq4 allele also conferred sensitivity to oxidative and thermal stresses, and lower male frequency (reflecting X-chromosome non-disjunction), traits reversed uniquely by rec-8 knockdown. A strain bearing the longer-lived lsq4 allele, differing from the short-lived strain at <0.3% of its genome, derived no lifespan or stress-survival benefit from rec-8 knockdown. We consider two possible explanations: high rec-8 expression may include increased “leaky” expression in mitotic cells, leading to deleterious destabilization of somatic genomes; or REC-8 may act entirely in germ-line meiotic cells to reduce aberrations such as non-disjunction, thereby blunting a stress-resistance response mediated by innate immunity. Replicative lifespan was extended 20% in haploid S. cerevisiae (BY4741) by deletion of REC8, orthologous to nematode rec-8, implying that REC8 disruption of mitotic-cell survival is widespread, exemplifying antagonistic pleiotropy (opposing effects on lifespan vs. reproduction), and/or balancing selection wherein genomic disruption increases genetic variation under harsh conditions.

A major QTL on mouse chromosome 17 resulting in lifespan variability in SOD1-G93A transgenic mouse models of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a late-onset degenerative disease affecting motor neurons in the spinal cord, brainstem, and motor cortex. There is great variation in the expression of ALS symptoms even between siblings who both carry the same Cu/Zn superoxide dismutase (SOD1) mutations. One important use of transgenic mouse models of SOD1-ALS is the study of genetic influences on ALS severity. We utilized multiple inbred mouse strains containing the SOD1-G93A transgene to demonstrate a major quantitative trait locus (QTL) on mouse chromosome 17 resulting in a significant shift in lifespan. Reciprocal crosses between long- and short-lived strains identified critical regions, and we have narrowed the area for potential genetic modifier(s) to < 2Mb of the genome. Results showed that resequencing of this region resulted in 28 candidate genes with potentially functional differences between strains. In conclusion, these studies provide the first major modifier locus affecting lifespan in this model of FALS and, once identified, these candidate modifier genes may provide insight into modifiers of human disease and, most importantly, define new targets for the development of therapies.

Live long and prosper: “Germline stem cell maintenance revisited” (retrospective on DOI: 10.1002/bies.201000085)

In many animals there is an apparent trade-off between reproduction and lifespan. Reproductive capacity is often determined by germ line stem cell (GLSC) function. These cells undergo self-renewing divisions to give rise to a gametogenic daughter cell that differentiates into one or more gametes, and a stem cell daughter that remains in the stem cell niche. If GLSC aging is slow or their mitoses are biased towards self-renewing conditions, then theymay last longer and enable animals to undergo late-life reproduction, associated with increased longevity. In contrast, if GLSC aging is rapid or their divisions tend to produce gametogenic daughters, then they may limit animals with such cells to early-life reproduction and shortened lifespan. Kazmarczyk and Kopp recently suggested that variation in GLSC maintenance may mediate this trade-off. Their hypothesis predicts that allelic variation in GLSC genes in short-lived strains would show bias towards “short term alleles” driving high, early-life expression of GLSC maintenance genes; in long-lived strains, “long term alleles” driving high, late-life expression of stem cell maintenance genes would predominate [1]. However, female flies from a longlived lineage show little change over their lifespan in expression levels of genes associated with oogenesis and stem cell division: they do not downregulate these genes with age, in contrast to shorterlived control females [2]. Moreover, there was no clear overlap between the results of this next generation sequencing study and an independent microarray-based

The short-lived annual fish Nothobranchius furzeri shows a typical teleost aging process reinforced by high incidence of age-dependent neoplasias

The annual fish Nothobranchius furzeri is the shortest-lived vertebrate which can be cultured in captivity. Here, we performed a histopathological analysis of age-related lesions in this species. Post-mortem analysis revealed lesions in liver (~90%), kidney (~75%), heart (~70%) and gonads (~40%) which are similar to those previously described in the small teleost Poecilia reticulata. In addition, a high incidence of neoplasias was observed in liver (~35%) and kidney (~25%).Different laboratory strains of N. furzeri show large genetic differences in longevity. Cross-sectional analysis revealed a clear age-dependent increase in the incidence of liver neoplasias which was accelerated in a short-lived strain. Cross-sectional analysis of gonads revealed sex-specific differences in the occurrence of lesions, with males being more severely affected than females.In conclusion, our analysis demonstrates that short life span in N. furzeri is a consequence of a typical teleost aging process which determines systemic failure of homeostasis functions rather than of a single organ or apparatus. Unlike other teleosts, however, this scenario is reinforced by high incidence of age-dependent neoplasias, making this species a promising model to analyze the molecular pathways of age-dependent spontaneous tumorigenesis.

Age‐related behavioral changes in Drosophila

Normal aging can be defined as the natural physiological changes that occur in an organism over time in the absence of any disease. Among the many age-related changes that can be observed are those that result in the progressive decline of a variety of behavioral responses, including locomotor activity and cognitive function. During the past decade, model organisms, such as the fruit fly Drosophila melanogaster, have been used extensively to study aging. These simpler model systems have been particularly useful for genetic studies of aging because of their small genome size, short generation time, and mean life span compared to either mice or humans. Drosophila also exhibits complex behaviors, many of which undergo age-related decline. Here, we describe the age-related changes in behavior that have been observed in Drosophila and discuss how these are affected in long- and short-lived strains of flies.

Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels

To better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 genetically-diverse inbred mouse strains housed in a specific pathogen-free facility. Clinical assessments were carried out every 6 months, measuring multiple age-related phenotypes including neuromuscular, kidney and heart function, body composition, bone density, hematology, hormonal levels, and immune system parameters. In a concurrent cross-sectional study of the same 31 strains at 6, 12, and 20 months, more invasive measurements were carried out followed by necropsy to assess apoptosis, DNA repair, chromosome fragility, and histopathology. In this report, which is the initial paper of a series, the study design, median lifespans, and circulating insulin-like growth factor 1 (IGF1) levels at 6, 12, and 18 months are described for the first cohort of 32 females and 32 males of each strain. Survival curves varied dramatically among strains with the median lifespans ranging from 251 to 964 days. Plasma IGF1 levels, which also varied considerably at each time point, showed an inverse correlation with a median lifespan at 6 months (R = -0.33, P = 0.01). This correlation became stronger if the short-lived strains with a median lifespan < 600 days were removed from the analysis (R = -0.53, P < 0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan.

Reduced TOR Signaling Extends Chronological Life Span via Increased Respiration and Upregulation of Mitochondrial Gene Expression

The relationships between mitochondrial respiration, reactive oxygen species (ROS), and life span are complex and remain controversial. Inhibition of the target of rapamycin (TOR) signaling pathway extends life span in several model organisms. We show here that deletion of the TOR1 gene extends chronological life span in Saccharomyces cerevisiae, primarily by increasing mitochondrial respiration via enhanced translation of mtDNA-encoded oxidative phosphorylation complex subunits. Unlike previously reported pathways regulating chronological life span, we demonstrate that deletion of TOR1 delays aging independently of the antioxidant gene SOD2. Furthermore, wild-type and tor1 null strains differ in life span only when respiration competent and grown in normoxia in the presence of glucose. We propose that inhibition of TOR signaling causes derepression of respiration during growth in glucose and that the subsequent increase in mitochondrial oxygen consumption limits intracellular oxygen and ROS-mediated damage during glycolytic growth, leading to lower cellular ROS and extension of chronological life span.

Effects of Overexpression of Copper-Zinc and Manganese Superoxide Dismutases, Catalase, and Thioredoxin Reductase Genes on Longevity in Drosophila melanogaster

The overexpression of antioxidative enzymes such as CuZn-superoxide dismutase (SOD), Mn-SOD, and catalase has previously been reported to extend life span in transgenic flies (Drosophila melanogaster). The purpose of this study was to determine whether life-extending effects persist if the recipient control strains of flies are relatively long-lived. Accordingly, the life spans of large numbers of replicate control and overexpressor lines were determined in two long-lived genetic backgrounds involving a combined total of >90,000 flies. Significant increases in the activities of both CuZn-SOD and catalase had no beneficial effect on survivorship in relatively long-lived y w mutant flies and were associated with slightly decreased life spans in wild type flies of the Oregon-R strain. The introduction of additional transgenes encoding Mn-SOD or thioredoxin reductase in the same genetic background also failed to cause life span extension. In conjunction with data from earlier studies, the results show that increasing the activities of these major antioxidative enzymes above wild type levels does not decrease the rate of aging in long-lived strains of Drosophila, although there may be some effect in relatively short-lived strains.

Mechanisms of aging: an appraisal of the oxidative stress hypothesis 1,2

The main purpose of this article is to provide a critical overview of the currently available evidence bearing on the validity of the oxidative stress hypothesis of aging, which postulates that senescence-associated attenuations in physiological functions are caused by molecular oxidative damage. Several lines of correlative evidence support the predictions of the hypothesis, e.g., macromolecular oxidative damage increases with age and tends to be associated with life expectancy of organisms. Nevertheless, a direct link between oxidative stress and aging has not as yet been established. Single gene mutations have been reported to extend the life spans of lower organisms, such as nematodes and insects; however, such prolongations of chronological clock time survival are usually associated with decreases in the rate of metabolism and reproductive output without affecting the metabolic potential, i.e., the total amount of energy consumed during life. Studies on genetic manipulations of the aging process have often been conducted on relatively short-lived strains that are physiologically weak, whereby life-span extensions can not be unambiguously assigned to a slowing effect on the rate of aging. It is concluded that although there is considerable evidence implicating oxidative stress in the aging process, additional evidence is needed to clearly define the nature of the involvement.

Age-associated DNA damage is accelerated in the senescence-accelerated mice

We investigated how the DNA status correlates with the aging process in organisms, in different organs and in tissues using two inbred strains of mice, which are genetically related but have different senescence patterns. The SAMP1 mice belong to an accelerated senescence-prone and short lived strain, the other, SAMR1 mice are from an accelerated senescence-resistant and long lived strain. Using the alkaline filter elution technique, pieces of tissues from six organs: lung, intestine, liver, brain, muscle, and heart have been examined for DNA damage, mainly DNA single strand breaks. It was shown that in newborns the DNA damage is minimal, and it was increased significantly with calendric age in all organs in both strains. Although the correlation of DNA damage with aging differed in the different six organs, damage was significantly higher in SAMP1 mice than SAMR1 mice at later life in all organs. This is another remarkable example for the strong correlation of DNA damage and aging process, especially with senescence acceleration.

Assessment of DNA-protein crosslinks in the course of aging in two mouse strains by use of a modified alkaline filter elution applied to whole tissue samples

Two different mouse strains have been used for determination of age dependence of DNA-protein crosslinks by alkaline filter elution: a long lived laboratory strain, NMRI and an accelerated senescence-prone, short lived strain, SAMP1. Five organs were selected: Brain, kidney, lung, heart and liver. Remarkably in all five organs of short lived SAMP1 mice crosslinks increased significantly with age. In NMRI however only in brain and heart a significant rise in old age has been observed, while in the other organs there was no increase in DNA-protein crosslinking. Appreciable mitotic activity which is lacking in brain and heart could be the reason for this difference. Poor repair in all five organs could be an important component for the multiple ailments and shortened life span in SAMP1 mice.